3FEE

The high resolution structure of human glutamate carboxypeptidase III (GCPIII/NAALADase II) in complex with quisqualic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.56 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.149 
  • R-Value Observed: 0.150 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Structural insight into the evolutionary and pharmacologic homology of glutamate carboxypeptidases II and III

Hlouchova, K.Barinka, C.Konvalinka, J.Lubkowski, J.

(2009) FEBS J 276: 4448-4462

  • DOI: https://doi.org/10.1111/j.1742-4658.2009.07152.x
  • Primary Citation of Related Structures:  
    3FEC, 3FED, 3FEE, 3FF3

  • PubMed Abstract: 

    Glutamate carboxypeptidase III (GCPIII) is a metalloenzyme that belongs to the transferrin receptor/glutamate carboxypeptidase II (GCPII; EC 3.4.17.21) superfamily. GCPIII has been studied mainly because of its evolutionary relationship to GCPII, an enzyme involved in a variety of neuropathologies and malignancies, such as glutamatergic neurotoxicity and prostate cancer. Given the potential functional and pharmacological overlap between GCPIII and GCPII, studies addressing the structural and physiological properties of GCPIII are crucial for obtaining a deeper understanding of the GCPII/GCPIII system. In the present study, we report high-resolution crystal structures of the human GCPIII ectodomain in a 'pseudo-unliganded' state and in a complex with: (a) L-glutamate (a product of hydrolysis); (b) a phosphapeptide transition state mimetic, namely (2S,3'S)-{[(3'-amino-3'-carboxy-propyl)-hydroxyphosphinoyl]methyl}-pentanedioic acid; and (c) quisqualic acid, a glutamate biostere. Our data reveal the overall fold and quaternary arrangement of the GCPIII molecule, define the architecture of the GCPIII substrate-binding cavity, and offer an experimental evidence for the presence of Zn(2+) ions in the bimetallic active site. Furthermore, the structures allow us to detail interactions between the enzyme and its ligands and to characterize the functional flexibility of GCPIII, which is essential for substrate recognition. A comparison of these GCPIII structures with the equivalent GCPII complexes reveals differences in the organization of specificity pockets, in surface charge distribution, and in the occupancy of the co-catalytic zinc sites. The data presented here provide information that should prove to be essential for the structurally-aided design of GCPIII-specific inhibitors and might comprise guidelines for future comparative GCPII/GCPIII studies.


  • Organizational Affiliation

    Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate carboxypeptidase III707Homo sapiensMutation(s): 0 
Gene Names: NAALAD2
EC: 3.4.17.21
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y3Q0 (Homo sapiens)
Explore Q9Y3Q0 
Go to UniProtKB:  Q9Y3Q0
PHAROS:  Q9Y3Q0
GTEx:  ENSG00000077616 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y3Q0
Sequence Annotations
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  • 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
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
QUS
Query on QUS

Download Ideal Coordinates CCD File 
J [auth A](S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID
C5 H7 N3 O5
ASNFTDCKZKHJSW-REOHCLBHSA-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 
I [auth A]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
H [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
QUS Binding MOAD:  3FEE Ki: 230 (nM) from 1 assay(s)
PDBBind:  3FEE Ki: 230 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.56 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.149 
  • R-Value Observed: 0.150 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 122.985α = 90
b = 103.69β = 108.27
c = 77.611γ = 90
Software Package:
Software NamePurpose
MAR345dtbdata collection
XFITdata reduction
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-08-25
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • 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: Data collection, Database references, Refinement description, Structure summary