8FJT

Human mitochondrial serine hydroxymethyltransferase (SHMT2) in complex with PLP, glycine and AGF362 inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.47 Å
  • R-Value Free: 0.285 
  • R-Value Work: 0.241 
  • R-Value Observed: 0.244 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Structure-Based Design of Transport-Specific Multitargeted One-Carbon Metabolism Inhibitors in Cytosol and Mitochondria.

Nayeen, M.J.Katinas, J.M.Magdum, T.Shah, K.Wong, J.E.O'Connor, C.E.Fifer, A.N.Wallace-Povirk, A.Hou, Z.Matherly, L.H.Dann 3rd, C.E.Gangjee, A.

(2023) J Med Chem 66: 11294-11323

  • DOI: https://doi.org/10.1021/acs.jmedchem.3c00763
  • Primary Citation of Related Structures:  
    8FJT, 8FJU, 8FJV, 8FJW, 8FJX, 8FJY

  • PubMed Abstract: 

    Multitargeted agents provide tumor selectivity with reduced drug resistance and dose-limiting toxicities. We previously described the multitargeted 6-substituted pyrrolo[3,2- d ]pyrimidine antifolate 1 with activity against early- and late-stage pancreatic tumors with limited tumor selectivity. Structure-based design with our human serine hydroxymethyl transferase (SHMT) 2 and glycinamide ribonucleotide formyltransferase (GARFTase) structures, and published X-ray crystal structures of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC), SHMT1, and folate receptor (FR) α and β afforded 11 analogues. Multitargeted inhibition and selective tumor transport were designed by providing promiscuous conformational flexibility in the molecules. Metabolite rescue identified mitochondrial C1 metabolism along with de novo purine biosynthesis as the targeted pathways. We identified analogues with tumor-selective transport via FRs and increased SHMT2, SHMT1, and GARFTase inhibition (28-, 21-, and 11-fold, respectively) compared to 1 . These multitargeted agents represent an exciting new structural motif for targeted cancer therapy with substantial advantages of selectivity and potency over clinically used antifolates.


  • Organizational Affiliation

    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine hydroxymethyltransferase, mitochondrial
A, B
493Homo sapiensMutation(s): 0 
Gene Names: SHMT2
EC: 2.1.2.1
UniProt & NIH Common Fund Data Resources
Find proteins for P34897 (Homo sapiens)
Explore P34897 
Go to UniProtKB:  P34897
PHAROS:  P34897
GTEx:  ENSG00000182199 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP34897
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
Y72 (Subject of Investigation/LOI)
Query on Y72

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B]
N-{4-[4-(2-amino-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-3-fluorothiophene-2-carbonyl}-L-glutamic acid
C20 H22 F N5 O6 S
HPZHEVFOCGGDJM-LBPRGKRZSA-N
PLG
Query on PLG

Download Ideal Coordinates CCD File 
C [auth A]N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE]
C10 H15 N2 O7 P
FEVQWBMNLWUBTF-UHFFFAOYSA-N
PLP
Query on PLP

Download Ideal Coordinates CCD File 
G [auth B]PYRIDOXAL-5'-PHOSPHATE
C8 H10 N O6 P
NGVDGCNFYWLIFO-UHFFFAOYSA-N
GLY
Query on GLY

Download Ideal Coordinates CCD File 
F [auth B]GLYCINE
C2 H5 N O2
DHMQDGOQFOQNFH-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.47 Å
  • R-Value Free: 0.285 
  • R-Value Work: 0.241 
  • R-Value Observed: 0.244 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 160.389α = 90
b = 160.389β = 90
c = 208.748γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesR01 CA250469

Revision History  (Full details and data files)

  • Version 1.0: 2023-09-06
    Type: Initial release
  • Version 2.0: 2024-02-07
    Type: Coordinate replacement
    Reason: Sequence discrepancy
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Refinement description, Structure summary