3IWW

Crystal structure of human glutamate carboxypeptidase II (GCPII) in a complex with DBIBzL, a urea-based inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Bioisosterism of urea-based GCPII inhibitors: Synthesis and structure-activity relationship studies.

Wang, H.Byun, Y.Barinka, C.Pullambhatla, M.Bhang, H.E.Fox, J.J.Lubkowski, J.Mease, R.C.Pomper, M.G.

(2010) Bioorg Med Chem Lett 20: 392-397

  • DOI: https://doi.org/10.1016/j.bmcl.2009.10.061
  • Primary Citation of Related Structures:  
    3IWW

  • PubMed Abstract: 

    We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure-activity relationship studies of the P1' site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with K(i) values below 20nM. Among them, compound 32d (K(i)=11nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1' pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d.


  • Organizational Affiliation

    Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate carboxypeptidase 2709Homo sapiensMutation(s): 0 
Gene Names: FOLH1FOLHNAALAD1PSMPSMA
EC: 3.4.17.21
UniProt & NIH Common Fund Data Resources
Find proteins for Q04609 (Homo sapiens)
Explore Q04609 
Go to UniProtKB:  Q04609
PHAROS:  Q04609
GTEx:  ENSG00000086205 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ04609
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
B, C, D
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
E
4N-Glycosylation
Glycosylation Resources
GlyTouCan:  G81315DD
GlyCosmos:  G81315DD
GlyGen:  G81315DD
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
YZE
Query on YZE

Download Ideal Coordinates CCD File 
M [auth A]N~2~-{[(1S)-1-carboxybut-3-en-1-yl]carbamoyl}-N~6~-[(4-iodophenyl)carbonyl]-L-lysine
C19 H24 I N3 O6
CPITYBQMVPBERS-GJZGRUSLSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A],
L [auth A]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
H [auth A]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
I [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
YZE PDBBind:  3IWW Ki: 11 (nM) from 1 assay(s)
BindingDB:  3IWW Ki: 11 (nM) from 1 assay(s)
Binding MOAD:  3IWW Ki: 11 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 101.068α = 90
b = 130.035β = 90
c = 157.951γ = 90
Software Package:
Software NamePurpose
MAR345data collection
REFMACrefinement
HKL-3000data reduction
HKL-3000data scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-11-24
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Advisory, Refinement description
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Structure summary
  • Version 2.1: 2023-09-06
    Changes: Advisory, Data collection, Database references, Refinement description, Structure summary