4R5A

A Carbonic Anhydrase IX Mimic in Complex with a Carbohydrate-Based Sulfamate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.157 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structural Insights into Carbonic Anhydrase IX Isoform Specificity of Carbohydrate-Based Sulfamates.

Moeker, J.Mahon, B.P.Bornaghi, L.F.Vullo, D.Supuran, C.T.McKenna, R.Poulsen, S.A.

(2014) J Med Chem 57: 8635-8645

  • DOI: https://doi.org/10.1021/jm5012935
  • Primary Citation of Related Structures:  
    4R59, 4R5A, 4R5B

  • PubMed Abstract: 

    Carbonic anhydrase IX (CA IX) is an extracellular transmembrane homodimeric zinc metalloenzyme that has been validated as a prognostic marker and therapeutic target for several types of aggressive cancers. CA IX shares a close homology with other CA isoforms, making the design of CA IX isoform selective inhibitors challenging. In this paper, we describe the development of a new class of CA IX inhibitors that comprise a sulfamate as the zinc binding group, a variable linker, and a carbohydrate "tail" moiety. Seven compounds inhibited CA IX with low nM Ki values of 1-2 nM and also exhibited permeability profiles to preferentially target the binding of extracellular CA IX over cytosolic CAs. The crystal structures of two of these compounds in complex with a CA IX-mimic (a variant of CA II, with active site residues that mimic CA IX) and one compound in complex with CA II have been determined to 1.7 Å resolution or better and demonstrate a selective mechanism of binding between the hydrophilic and hydrophobic pockets of CA IX versus CA II. These compounds present promising candidates for anti-CA IX drugs and the treatment for several aggressive cancer types.


  • Organizational Affiliation

    Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2260Homo sapiensMutation(s): 7 
Gene Names: CA2
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00918 (Homo sapiens)
Explore P00918 
Go to UniProtKB:  P00918
PHAROS:  P00918
GTEx:  ENSG00000104267 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00918
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3J4
Query on 3J4

Download Ideal Coordinates CCD File 
D [auth A](6S)-2,6-anhydro-6-{[(3R)-3-(sulfamoyloxy)pyrrolidin-1-yl]sulfonyl}-D-glucitol
C10 H20 N2 O10 S2
TWZVGIAZMOMKML-NGXNFIGVSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
ALY
Query on ALY
A
L-PEPTIDE LINKINGC8 H16 N2 O3LYS
Binding Affinity Annotations 
IDSourceBinding Affinity
3J4 Binding MOAD:  4R5A Ki: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.157 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.038α = 90
b = 41.429β = 103.79
c = 72.259γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-10-15
    Type: Initial release
  • Version 1.1: 2014-11-12
    Changes: Database references
  • Version 1.2: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Database references, Derived calculations
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Refinement description
  • Version 1.4: 2023-12-06
    Changes: Data collection