5DIE

Crystal Structure of the ER-alpha Ligand-binding Domain in complex with a trifluoro-substituted A-CD ring estrogen derivative (1S,3aR,5S,7aS)-7a-methyl-5-(2,3,5-trifluoro-4-hydroxyphenyl)octahydro-1H-inden-1-ol

External Resource: Annotation

Domain Annotation: SCOP2 Classification
Domain Annotation: ECOD Classification
Domain Annotation: CATH
Protein Family Annotation
Gene Ontology: Gene Product Annotation
InterPro: Protein Family Classification
Pharos: Disease Associations

Domain Annotation: SCOP2 Classification SCOP2 Database Homepage

Chains	Type	Family Name	Domain Identifier	Family Identifier	Provenance Source (Version)
B	SCOP2B Superfamily	Nuclear receptor ligand-binding domain	8044103	3001442	SCOP2B (2022-06-29)
A	SCOP2B Superfamily	Nuclear receptor ligand-binding domain	8044103	3001442	SCOP2B (2022-06-29)

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
B	Hormone_recep_1	e5dieB1	A: alpha arrays	X: Nuclear receptor ligand-binding domain (From Topology)	H: Nuclear receptor ligand-binding domain (From Topology)	T: Nuclear receptor ligand-binding domain	F: Hormone_recep_1	ECOD (1.6)
A	Hormone_recep_1	e5dieA1	A: alpha arrays	X: Nuclear receptor ligand-binding domain (From Topology)	H: Nuclear receptor ligand-binding domain (From Topology)	T: Nuclear receptor ligand-binding domain	F: Hormone_recep_1	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
B	1.10.565.10	Mainly Alpha	Orthogonal Bundle	Retinoid X Receptor	Retinoid X Receptor	CATH (4.3.0)
A	1.10.565.10	Mainly Alpha	Orthogonal Bundle	Retinoid X Receptor	Retinoid X Receptor	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A, B	PF00104	Ligand-binding domain of nuclear hormone receptor (Hormone_recep)	Ligand-binding domain of nuclear hormone receptor	This all helical domain is involved in binding the hormone in these receptors.	Domain

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A, B	Estrogen receptor	transcription factor binding basal transcription machinery binding protein binding binding basal RNA polymerase II transcription machinery binding general transcription initiation factor binding RNA polymerase II general transcription initiation factor binding TFIIB-class transcription factor binding transcription coregulator binding 14-3-3 protein binding DNA-binding transcription factor activity, RNA polymerase II-specific transcription regulator activity DNA-binding transcription factor activity DNA binding transcription factor binding basal transcription machinery binding protein binding binding basal RNA polymerase II transcription machinery binding general transcription initiation factor binding RNA polymerase II general transcription initiation factor binding TFIIB-class transcription factor binding transcription coregulator binding 14-3-3 protein binding DNA-binding transcription factor activity, RNA polymerase II-specific transcription regulator activity DNA-binding transcription factor activity DNA binding sequence-specific DNA binding double-stranded DNA binding nucleic acid binding RNA polymerase II transcription regulatory region sequence-specific DNA binding cis-regulatory region sequence-specific DNA binding sequence-specific double-stranded DNA binding transcription cis-regulatory region binding organic cyclic compound binding estrogen response element binding transcription regulatory region nucleic acid binding RNA polymerase II cis-regulatory region sequence-specific DNA binding TBP-class protein binding enzyme regulator activity molecular function regulator activity nitric-oxide synthase regulator activity nuclear receptor activity molecular transducer activity ligand-activated transcription factor activity signaling receptor activity calmodulin binding DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription activator activity ATPase binding enzyme binding identical protein binding transcription corepressor binding chromatin binding nuclear steroid receptor activity nuclear estrogen receptor activity G protein-coupled receptor activity transmembrane signaling receptor activity G protein-coupled estrogen receptor activity kinase binding protein kinase binding transcription coactivator binding steroid binding lipid binding beta-catenin binding cation binding transition metal ion binding zinc ion binding ion binding metal ion binding small molecule binding RNA polymerase II-specific DNA-binding transcription factor binding nuclear receptor binding DNA-binding transcription factor binding nuclear estrogen receptor binding	developmental process multicellular organismal process gonad development reproductive system development reproductive process sex differentiation animal organ development developmental process involved in reproduction male gonad development male sex differentiation multicellular organism development development of primary male sexual characteristics development of primary sexual characteristics anatomical structure development reproductive structure development developmental process multicellular organismal process gonad development reproductive system development reproductive process sex differentiation animal organ development developmental process involved in reproduction male gonad development male sex differentiation multicellular organism development development of primary male sexual characteristics development of primary sexual characteristics anatomical structure development reproductive structure development system development regulation of biosynthetic process regulation of nitric oxide biosynthetic process regulation of biological process biological regulation positive regulation of biological process reactive nitrogen species metabolic process positive regulation of nitric oxide metabolic process nitric oxide metabolic process positive regulation of metabolic process nitric oxide biosynthetic process biosynthetic process positive regulation of biosynthetic process metabolic process regulation of nitric oxide metabolic process positive regulation of nitric oxide biosynthetic process regulation of metabolic process cellular biosynthetic process transcription preinitiation complex assembly RNA metabolic process cellular component organization cellular component biogenesis protein-DNA complex organization RNA biosynthetic process nucleobase-containing compound metabolic process DNA-templated transcription nucleic acid biosynthetic process cellular component assembly transcription by RNA polymerase II protein-containing complex assembly cellular component organization or biogenesis transcription initiation at RNA polymerase II promoter protein-containing complex organization cellular metabolic process protein-DNA complex assembly primary metabolic process nucleobase-containing compound biosynthetic process gene expression macromolecule biosynthetic process DNA-templated transcription initiation nucleic acid metabolic process RNA polymerase II preinitiation complex assembly cellular process macromolecule metabolic process regulation of catalytic activity positive regulation of catalytic activity regulation of oxidoreductase activity positive regulation of oxidoreductase activity positive regulation of nitric-oxide synthase activity regulation of molecular function positive regulation of molecular function regulation of monooxygenase activity positive regulation of monooxygenase activity regulation of nitric-oxide synthase activity regulation of hormone levels steroid metabolic process androgen metabolic process regulation of biological quality hormone metabolic process lipid metabolic process positive regulation of DNA-binding transcription factor activity regulation of cellular process regulation of primary metabolic process regulation of RNA metabolic process regulation of nucleobase-containing compound metabolic process regulation of RNA biosynthetic process regulation of cellular metabolic process regulation of macromolecule metabolic process regulation of cellular biosynthetic process regulation of gene expression regulation of DNA-binding transcription factor activity regulation of macromolecule biosynthetic process regulation of DNA-templated transcription cellular response to stimulus response to lipid response to stimulus signaling hormone-mediated signaling pathway cell communication cellular response to endogenous stimulus response to hormone response to steroid hormone signal transduction cellular response to steroid hormone stimulus response to organic cyclic compound steroid hormone receptor signaling pathway cellular response to hormone stimulus response to endogenous stimulus cellular response to organic cyclic compound cellular response to chemical stimulus response to chemical cellular response to lipid regulation of epithelial cell apoptotic process regulation of apoptotic process regulation of programmed cell death cell death epithelial cell apoptotic process apoptotic process programmed cell death positive regulation of response to biotic stimulus pattern recognition receptor signaling pathway toll-like receptor signaling pathway regulation of signal transduction response to biotic stimulus immune response-activating signaling pathway positive regulation of immune response regulation of immune system process positive regulation of immune system process innate immune response-activating signaling pathway immune response response to other organism regulation of innate immune response response to external stimulus regulation of response to stimulus defense response to other organism regulation of pattern recognition receptor signaling pathway positive regulation of defense response activation of innate immune response regulation of immune response regulation of toll-like receptor signaling pathway activation of immune response regulation of defense response regulation of response to biotic stimulus biological process involved in interspecies interaction between organisms regulation of response to external stimulus positive regulation of response to stimulus positive regulation of response to external stimulus immune response-regulating signaling pathway regulation of response to stress response to stress innate immune response response to external biotic stimulus regulation of signaling positive regulation of innate immune response defense response defense response to symbiont immune system process regulation of cell communication fibroblast proliferation cell population proliferation intracellular receptor signaling pathway intracellular signal transduction nuclear receptor-mediated steroid hormone signaling pathway estrogen receptor signaling pathway nuclear receptor-mediated signaling pathway phospholipase C-activating G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway prostate gland development developmental growth gland development organ growth prostate gland epithelium morphogenesis gland morphogenesis animal organ morphogenesis prostate gland morphogenetic growth prostate gland growth epithelium development axis elongation branch elongation of an epithelium growth morphogenesis of an epithelium urogenital system development tissue development developmental growth involved in morphogenesis prostate gland morphogenesis tissue morphogenesis anatomical structure morphogenesis morphogenesis of a branching structure branching involved in prostate gland morphogenesis prostate epithelial cord elongation morphogenesis of a branching epithelium response to estrogen cellular response to estrogen stimulus negative regulation of biological process negative regulation of cellular metabolic process negative regulation of RNA biosynthetic process negative regulation of cellular process negative regulation of nucleobase-containing compound metabolic process negative regulation of macromolecule metabolic process regulation of transcription by RNA polymerase II negative regulation of DNA-templated transcription negative regulation of transcription by RNA polymerase II negative regulation of metabolic process negative regulation of cellular biosynthetic process negative regulation of biosynthetic process negative regulation of macromolecule biosynthetic process negative regulation of RNA metabolic process ovulation cycle process development of primary female sexual characteristics ovulation cycle ovarian follicle development rhythmic process female gonad development multicellular organismal reproductive process female sex differentiation antral ovarian follicle growth positive regulation of DNA-templated transcription positive regulation of cellular metabolic process positive regulation of macromolecule biosynthetic process positive regulation of macromolecule metabolic process positive regulation of cellular process positive regulation of nucleobase-containing compound metabolic process positive regulation of transcription by RNA polymerase II positive regulation of RNA metabolic process positive regulation of RNA biosynthetic process positive regulation of cellular biosynthetic process epithelial cell development cellular developmental process cell differentiation cell development epithelial cell differentiation positive regulation of cytosolic calcium ion concentration negative regulation of DNA-binding transcription factor activity negative regulation of molecular function genitalia development female genitalia development vagina development negative regulation of signaling negative regulation of intracellular signal transduction negative regulation of canonical NF-kappaB signal transduction negative regulation of cell communication regulation of intracellular signal transduction intracellular signaling cassette negative regulation of response to stimulus negative regulation of signal transduction canonical NF-kappaB signal transduction regulation of canonical NF-kappaB signal transduction positive regulation of cell population proliferation regulation of fibroblast proliferation regulation of cell population proliferation positive regulation of fibroblast proliferation protein localization localization protein localization to chromatin cellular localization protein localization to chromosome protein localization to organelle cellular macromolecule localization macromolecule localization branching involved in mammary gland duct morphogenesis multi-multicellular organism process mammary gland morphogenesis maternal process involved in female pregnancy mammary gland development branching morphogenesis of an epithelial tube tube morphogenesis mammary gland branching involved in pregnancy epithelial tube morphogenesis female pregnancy tube development mammary gland duct morphogenesis mammary gland epithelium development multi-organism reproductive process negative regulation of miRNA transcription regulation of miRNA metabolic process miRNA metabolic process miRNA transcription negative regulation of miRNA metabolic process regulation of miRNA transcription uterus development branch elongation involved in mammary gland duct branching epithelial cell proliferation involved in mammary gland duct elongation epithelial cell proliferation mammary gland epithelial cell proliferation regulation of inflammatory response inflammatory response prostate glandular acinus development prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis prostate glandular acinus morphogenesis response to oxygen-containing compound cellular response to oxygen-containing compound response to estradiol cellular response to estradiol stimulus negative regulation of gene expression stem cell differentiation regulation of developmental process regulation of reproductive process regulation of morphogenesis of an epithelium regulation of multicellular organismal process regulation of anatomical structure morphogenesis regulation of morphogenesis of a branching structure regulation of branching involved in prostate gland morphogenesis mammary gland lobule development mammary gland alveolus development chromatin organization chromatin remodeling muscle cell apoptotic process smooth muscle cell apoptotic process negative regulation of programmed cell death regulation of muscle cell apoptotic process regulation of smooth muscle cell apoptotic process negative regulation of smooth muscle cell apoptotic process negative regulation of apoptotic process negative regulation of muscle cell apoptotic process	membrane cellular anatomical entity intracellular anatomical structure cytoplasm cytosol protein-containing complex transcription regulator complex intracellular organelle organelle intracellular non-membrane-bounded organelle chromatin chromosome non-membrane-bounded organelle membrane-bounded organelle membrane cellular anatomical entity intracellular anatomical structure cytoplasm cytosol protein-containing complex transcription regulator complex intracellular organelle organelle intracellular non-membrane-bounded organelle chromatin chromosome non-membrane-bounded organelle membrane-bounded organelle Golgi apparatus intracellular membrane-bounded organelle endomembrane system cell periphery plasma membrane nucleus membrane-enclosed lumen intracellular organelle lumen nucleoplasm organelle lumen nuclear lumen euchromatin
C, D	Nuclear receptor coactivator 2	protein binding binding protein domain specific binding DNA binding sequence-specific DNA binding double-stranded DNA binding nucleic acid binding RNA polymerase II transcription regulatory region sequence-specific DNA binding cis-regulatory region sequence-specific DNA binding sequence-specific double-stranded DNA binding transcription cis-regulatory region binding organic cyclic compound binding transcription regulatory region nucleic acid binding RNA polymerase II cis-regulatory region sequence-specific DNA binding protein binding binding protein domain specific binding DNA binding sequence-specific DNA binding double-stranded DNA binding nucleic acid binding RNA polymerase II transcription regulatory region sequence-specific DNA binding cis-regulatory region sequence-specific DNA binding sequence-specific double-stranded DNA binding transcription cis-regulatory region binding organic cyclic compound binding transcription regulatory region nucleic acid binding RNA polymerase II cis-regulatory region sequence-specific DNA binding chromatin binding transcription coactivator activity transcription regulator activity transcription coregulator activity protein-macromolecule adaptor activity molecular adaptor activity transcription factor binding RNA polymerase II-specific DNA-binding transcription factor binding nuclear receptor binding DNA-binding transcription factor binding RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding intronic transcription regulatory region sequence-specific DNA binding nuclear receptor coactivator activity protein dimerization activity signaling receptor binding aryl hydrocarbon receptor binding	regulation of biological process regulation of lipid metabolic process biological regulation primary metabolic process metabolic process regulation of metabolic process lipid metabolic process regulation of primary metabolic process developmental process multicellular organismal process regulation of developmental process connective tissue development adipose tissue development positive regulation of adipose tissue development regulation of biological process regulation of lipid metabolic process biological regulation primary metabolic process metabolic process regulation of metabolic process lipid metabolic process regulation of primary metabolic process developmental process multicellular organismal process regulation of developmental process connective tissue development adipose tissue development positive regulation of adipose tissue development animal organ development positive regulation of biological process tissue development positive regulation of developmental process regulation of adipose tissue development anatomical structure development positive regulation of multicellular organismal process regulation of multicellular organismal process response to ketone response to lipid response to stimulus response to hormone response to steroid hormone response to chemical response to endogenous stimulus response to progesterone response to oxygen-containing compound response to organic cyclic compound cellular response to stimulus cellular response to endogenous stimulus cellular response to chemical stimulus cellular process cellular response to hormone stimulus regulation of biosynthetic process rhythmic process regulation of cellular process circadian regulation of gene expression cellular biosynthetic process cellular metabolic process circadian rhythm regulation of cellular metabolic process regulation of macromolecule metabolic process gene expression macromolecule biosynthetic process regulation of cellular biosynthetic process regulation of gene expression biosynthetic process regulation of macromolecule biosynthetic process macromolecule metabolic process RNA metabolic process nucleobase-containing compound metabolic process RNA biosynthetic process nucleic acid biosynthetic process DNA-templated transcription regulation of RNA metabolic process regulation of nucleobase-containing compound metabolic process regulation of RNA biosynthetic process nucleobase-containing compound biosynthetic process nucleic acid metabolic process regulation of DNA-templated transcription intracellular receptor signaling pathway signaling intracellular signal transduction cell communication peroxisome proliferator activated receptor signaling pathway signal transduction nuclear receptor-mediated signaling pathway mRNA transcription by RNA polymerase II mRNA transcription mRNA metabolic process transcription by RNA polymerase II behavior circadian behavior locomotory behavior rhythmic behavior locomotor rhythm response to Thyroglobulin triiodothyronine cellular response to Thyroglobulin triiodothyronine negative regulation of biological process negative regulation of cellular metabolic process negative regulation of RNA biosynthetic process negative regulation of cellular process negative regulation of nucleobase-containing compound metabolic process negative regulation of macromolecule metabolic process regulation of transcription by RNA polymerase II negative regulation of DNA-templated transcription negative regulation of transcription by RNA polymerase II negative regulation of metabolic process negative regulation of cellular biosynthetic process negative regulation of biosynthetic process negative regulation of macromolecule biosynthetic process negative regulation of RNA metabolic process cellular response to nitrogen compound response to peptide hormone cellular response to peptide hormone stimulus response to nitrogen compound regulation of cellular response to insulin stimulus cellular response to oxygen-containing compound regulation of response to stimulus response to insulin cellular response to insulin stimulus positive regulation of DNA-templated transcription positive regulation of cellular metabolic process positive regulation of macromolecule biosynthetic process positive regulation of metabolic process positive regulation of biosynthetic process positive regulation of macromolecule metabolic process positive regulation of cellular process positive regulation of nucleobase-containing compound metabolic process positive regulation of transcription by RNA polymerase II positive regulation of RNA metabolic process positive regulation of RNA biosynthetic process positive regulation of cellular biosynthetic process monosaccharide metabolic process carbohydrate metabolic process hexose metabolic process regulation of small molecule metabolic process small molecule metabolic process regulation of carbohydrate metabolic process regulation of glucose metabolic process glucose metabolic process	RNA polymerase II transcription regulator complex membrane-bounded organelle protein-containing complex intracellular anatomical structure nucleus nuclear protein-containing complex transcription regulator complex intracellular membrane-bounded organelle cellular anatomical entity intracellular organelle organelle cytoplasm membrane-enclosed lumen intracellular organelle lumen RNA polymerase II transcription regulator complex membrane-bounded organelle protein-containing complex intracellular anatomical structure nucleus nuclear protein-containing complex transcription regulator complex intracellular membrane-bounded organelle cellular anatomical entity intracellular organelle organelle cytoplasm membrane-enclosed lumen intracellular organelle lumen nucleoplasm organelle lumen nuclear lumen intracellular non-membrane-bounded organelle chromatin chromosome non-membrane-bounded organelle nuclear body

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A, B	IPR001628	Zinc finger, nuclear hormone receptor-type	Domain
A, B	IPR050200	Nuclear hormone receptor family NR3 subfamily	Family
A, B	IPR013088	Zinc finger, NHR/GATA-type	Homologous Superfamily
A, B	IPR024736	Oestrogen-type nuclear receptor final C-terminal domain	Domain
A, B	IPR001292	Estrogen receptor	Family
A, B	IPR024178	Estrogen receptor/oestrogen-related receptor	Family
A, B	IPR001723	Nuclear hormone receptor	Family
A, B	IPR046944	Estrogen receptor, N-terminal	Domain
A, B	IPR000536	Nuclear hormone receptor, ligand-binding domain	Domain
A, B	IPR035500	Nuclear hormone receptor-like domain superfamily	Homologous Superfamily
C, D	IPR010011	Nuclear receptor coactivator, DUF1518	Domain
C, D	IPR009110	Nuclear receptor coactivator, interlocking	Homologous Superfamily
C, D	IPR037077	Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily	Homologous Superfamily
C, D	IPR017426	Nuclear receptor coactivator	Family
C, D	IPR014935	Nuclear receptor coactivator, receptor-binding domain	Domain
C, D	IPR013767	PAS fold	Domain
C, D	IPR000014	PAS domain	Domain
C, D	IPR011598	Myc-type, basic helix-loop-helix (bHLH) domain	Domain
C, D	IPR014920	Nuclear receptor coactivator, Ncoa-type, interlocking	Domain
C, D	IPR035965	PAS domain superfamily	Homologous Superfamily
C, D	IPR028822	Nuclear receptor coactivator 2, basic helix-loop-helix	Domain
C, D	IPR032565	Nuclear receptor coactivator 2/3, DUF4927	Domain
C, D	IPR036638	Helix-loop-helix DNA-binding domain superfamily	Homologous Superfamily

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
A, B	Pharos: P03372	breast carcinoma uterine corpus leiomyoma prostate cancer estrogen resistance syndrome carcinoma obesity disorder Alzheimer disease bone disease breast cancer female infertility glomerulonephritis migraine with or without aura, susceptibility to, 1 leiomyoma Musculoskeletal Pain lung cancer breast carcinoma uterine corpus leiomyoma prostate cancer estrogen resistance syndrome carcinoma obesity disorder Alzheimer disease bone disease breast cancer female infertility glomerulonephritis migraine with or without aura, susceptibility to, 1 leiomyoma Musculoskeletal Pain lung cancer protoplasmic astrocytoma male infertility fibrillary astrocytoma coronary artery disease tubular adenocarcinoma astrocytic tumor urinary bladder cancer pilocytic astrocytoma atherosclerosis leukemia myocardial infarction prostate intraepithelial neoplasia adenocarcinoma oligospermia sarcomatoid carcinoma gemistocytic astrocytoma subependymal giant cell astrocytoma granular cell carcinoma hereditary breast carcinoma juvenile pilocytic astrocytoma liver cancer endometrial carcinoma endometriosis neuroblastoma childhood cerebral astrocytoma anaplastic astrocytoma diffuse astrocytoma peripheral neuropathy migraine disorder ductal breast carcinoma in situ benign mesothelioma endogenous depression endometrial hyperplasia cardiac arrest colorectal cancer ovarian cancer cystic fibrosis pancreatic intraductal papillary-mucinous neoplasm with low grade dysplasia hepatocellular carcinoma mesothelioma infertility disorder postmenopausal osteoporosis invasive ductal breast carcinoma bipolar disorder endometrial cancer liver neoplasm breast adenocarcinoma estrogen-receptor negative breast cancer psoriasis adrenal cortex carcinoma osteoporosis ovarian carcinoma amelogenesis imperfecta type 1G cribriform carcinoma pancreatic intraductal papillary-mucinous carcinoma undifferentiated carcinoma depressive disorder peripheral nervous system disease astrocytoma (excluding glioblastoma) urinary bladder neoplasm pituitary cancer interstitial cystitis atopic eczema drug psychosis attention deficit hyperactivity disorder, inattentive type primary ovarian failure lung benign neoplasm male breast carcinoma cancer malignant mesothelioma cerebral astrocytoma osteogenesis imperfecta schizophrenia osteosarcoma mammary neoplasms, animal ovarian neoplasm cribriform carcinoma of breast pancreatic intraductal papillary-mucinous neoplasm arteriosclerosis disorder
C, D	Pharos: Q15596	breast carcinoma prostate cancer psoriasis ulcerative colitis adenoma endometriosis interstitial cystitis Mammary Neoplasms osteosarcoma testicular cancer atypical teratoid rhabdoid tumor Crohn disease Gaucher disease large cell medulloblastoma pancreatic intraductal papillary-mucinous neoplasm breast carcinoma prostate cancer psoriasis ulcerative colitis adenoma endometriosis interstitial cystitis Mammary Neoplasms osteosarcoma testicular cancer atypical teratoid rhabdoid tumor Crohn disease Gaucher disease large cell medulloblastoma pancreatic intraductal papillary-mucinous neoplasm testicular germ cell tumor breast cancer endogenous depression glioblastoma medulloblastoma plasma cell myeloma