4ZZ1

HUMAN GAR TRANSFORMYLASE IN COMPLEX WITH GAR AND (S)-2-({4-[3-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-6-YL)-PROPYL]-THIOPHENE-2-CARBONYL}-AMINO)-PENTANEDIOIC ACID


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.158 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.140 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor alpha and the Proton-Coupled Folate Transporter in Human Tumors.

Wang, L.Wallace, A.Raghavan, S.Deis, S.M.Wilson, M.R.Yang, S.Polin, L.White, K.Kushner, J.Orr, S.George, C.O'Connor, C.Hou, Z.Mitchell-Ryan, S.Dann, C.E.Matherly, L.H.Gangjee, A.

(2015) J Med Chem 58: 6938-6959

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00801
  • Primary Citation of Related Structures:  
    4ZZ1, 4ZZ2, 4ZZ3

  • PubMed Abstract: 

    2-Amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine antifolate thiophene regioisomers of AGF94 (4) with a thienoyl side chain and three-carbon bridge lengths [AGF150 (5) and AGF154 (7)] were synthesized as potential antitumor agents. These analogues inhibited proliferation of Chinese hamster ovary (CHO) sublines expressing folate receptors (FRs) α or β (IC50s < 1 nM) or the proton-coupled folate transporter (PCFT) (IC50 < 7 nM). Compounds 5 and 7 inhibited KB, IGROV1, and SKOV3 human tumor cells at subnanomolar concentrations, reflecting both FRα and PCFT uptake. AGF152 (6) and AGF163 (8), 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine thiophene regioisomers, also inhibited growth of FR-expressing CHO and KB cells. All four analogues inhibited glycinamide ribonucleotide formyltransferase (GARFTase). Crystal structures of human GARFTase complexed with 5 and 7 were reported. In severe combined immunodeficient mice bearing SKOV3 tumors, 7 was efficacious. The selectivity of these compounds for PCFT and for FRα and β over the ubiquitously expressed reduced folate carrier is a paradigm for selective tumor targeting.


  • Organizational Affiliation

    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Trifunctional purine biosynthetic protein adenosine-3210Homo sapiensMutation(s): 0 
Gene Names: GARTPGFTPRGS
EC: 6.3.4.13 (PDB Primary Data), 6.3.3.1 (PDB Primary Data), 2.1.2.2 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P22102 (Homo sapiens)
Explore P22102 
Go to UniProtKB:  P22102
PHAROS:  P22102
GTEx:  ENSG00000159131 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22102
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3YF
Query on 3YF

Download Ideal Coordinates CCD File 
C [auth A](S)-2-({4-[3-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-propyl]-thiophene-2-carbonyl}-amino)-pentanedioic acid
C19 H21 N5 O6 S
UNSSSMUKJOLMJV-LBPRGKRZSA-N
GAR
Query on GAR

Download Ideal Coordinates CCD File 
B [auth A]GLYCINAMIDE RIBONUCLEOTIDE
C7 H13 N2 O8 P
OBQMLSFOUZUIOB-SHUUEZRQSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.158 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.140 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.344α = 90
b = 75.344β = 90
c = 100.736γ = 120
Software Package:
Software NamePurpose
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
Cootmodel building
HKL-2000data reduction

Structure Validation

View Full Validation Report



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 StatesGM094472
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA166711

Revision History  (Full details and data files)

  • Version 1.0: 2015-12-16
    Type: Initial release
  • Version 1.1: 2017-09-20
    Changes: Author supporting evidence, Database references, Derived calculations
  • Version 1.2: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.3: 2023-09-27
    Changes: Data collection, Database references, Refinement description