7L1A

Human Methionine Adenosyltransferase 2A bound to Methylthioadenosine and inhibitor, di-imido triphosphate (PNPNP)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.25 Å
  • R-Value Free: 0.141 
  • R-Value Work: 0.123 
  • R-Value Observed: 0.124 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A.

Niland, C.N.Ghosh, A.Cahill, S.M.Schramm, V.L.

(2021) Biochemistry 60: 791-801

  • DOI: https://doi.org/10.1021/acs.biochem.0c00998
  • Primary Citation of Related Structures:  
    7L1A

  • PubMed Abstract: 

    S -Adenosyl-l-methionine (AdoMet) is synthesized by the MAT2A isozyme of methionine adenosyltransferase in most human tissues and in cancers. Its contribution to epigenetic control has made it a target for anticancer intervention. A recent kinetic isotope effect analysis of MAT2A demonstrated a loose nucleophilic transition state. Here we show that MAT2A has a sequential mechanism with a rate-limiting step of formation of AdoMet, followed by rapid hydrolysis of the β-γ bond of triphosphate, and rapid release of phosphate and pyrophosphate. MAT2A catalyzes the slow hydrolysis of both ATP and triphosphate in the absence of other reactants. Positional isotope exchange occurs with 18 O as the 5'-oxygen of ATP. Loss of the triphosphate is sufficiently reversible to permit rotation and recombination of the α-phosphoryl group of ATP. Adenosine (α-β or β-γ)-imido triphosphates are slow substrates, and the respective imido triphosphates are inhibitors. The hydrolytically stable (α-β, β-γ)-diimido triphosphate (PNPNP) is a nanomolar inhibitor. The MAT2A protein structure is highly stabilized against denaturation by binding of PNPNP. A crystal structure of MAT2A with 5'-methylthioadenosine and PNPNP shows the ligands arranged appropriately in the ATP binding site. Two magnesium ions chelate the α- and γ-phosphoryl groups of PNPNP. The β-phosphoryl oxygen is in contact with an essential potassium ion. Imidophosphate derivatives provide contact models for the design of catalytic site ligands for MAT2A.


  • Organizational Affiliation

    Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
S-adenosylmethionine synthase isoform type-2417Homo sapiensMutation(s): 0 
Gene Names: MAT2AAMS2MATA2
EC: 2.5.1.6
UniProt & NIH Common Fund Data Resources
Find proteins for P31153 (Homo sapiens)
Explore P31153 
Go to UniProtKB:  P31153
PHAROS:  P31153
GTEx:  ENSG00000168906 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP31153
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MTA
Query on MTA

Download Ideal Coordinates CCD File 
F [auth A]5'-DEOXY-5'-METHYLTHIOADENOSINE
C11 H15 N5 O3 S
WUUGFSXJNOTRMR-IOSLPCCCSA-N
XE1
Query on XE1

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E [auth A]N,N'-(dihydroxy-lambda~5~-phosphanediyl)bis(phosphoramidic acid)
H9 N2 O8 P3
ODGUPQBDYZTXCT-UHFFFAOYSA-N
ALA
Query on ALA

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G [auth A]ALANINE
C3 H7 N O2
QNAYBMKLOCPYGJ-REOHCLBHSA-N
K
Query on K

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D [auth A]POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
MG
Query on MG

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B [auth A],
C [auth A]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
NA
Query on NA

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H [auth A]
I [auth A]
J [auth A]
K [auth A]
L [auth A]
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.25 Å
  • R-Value Free: 0.141 
  • R-Value Work: 0.123 
  • R-Value Observed: 0.124 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.113α = 90
b = 94.148β = 90
c = 117.237γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Aimlessdata scaling
PHASERphasing
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM041916
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA225149

Revision History  (Full details and data files)

  • Version 1.0: 2021-03-17
    Type: Initial release
  • Version 1.1: 2021-03-31
    Changes: Database references
  • Version 1.2: 2023-10-18
    Changes: Data collection, Database references, Derived calculations, Refinement description