4ZWY

Human Carbonic Anhydrase II in complex with a glucosyl sulfamate inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.173 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.156 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX Using Structure-Activity Relationships of Glucosyl-Based Sulfamates.

Mahon, B.P.Lomelino, C.L.Ladwig, J.Rankin, G.M.Driscoll, J.M.Salguero, A.L.Pinard, M.A.Vullo, D.Supuran, C.T.Poulsen, S.A.McKenna, R.

(2015) J Med Chem 58: 6630-6638

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00845
  • Primary Citation of Related Structures:  
    4ZWX, 4ZWY, 4ZWZ, 4ZX0, 4ZX1

  • PubMed Abstract: 

    Inhibition of human carbonic anhydrase IX (hCA IX) has shown to be therapeutically advantageous for treating many types of highly aggressive cancers. However, designing selective inhibitors for hCA IX has been difficult due to its high structural homology and sequence similarity with off-target hCAs. Recently, the use of glucosyl sulfamate inhibitors has shown promise as selective inhibitors for hCA IX. In this study, we present five X-ray crystal structures, determined to a resolution of 1.7 Å or better, of both hCA II (a ubiquitous CA) and an engineered hCA IX-mimic in complex with selected glucosyl sulfamates and structurally rationalize mechanisms for hCA IX selectivity. Results from this study have allowed us, for the first time, to empirically "map" key interactions of the hCA IX active site in order to establish parameters needed to design novel hCA IX selective inhibitors.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , 1600 SW Archer Road, PO Box 100245, Gainesville, Florida 32610, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2257Homo sapiensMutation(s): 0 
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
4SN
Query on 4SN

Download Ideal Coordinates CCD File 
C [auth A](6S)-1,3,4,5-tetra-O-acetyl-2,6-anhydro-6-{[5-(sulfamoyloxy)pentyl]sulfamoyl}-L-altritol
C19 H32 N2 O14 S2
CXIJBWKOZIQDPV-VHPHOLNESA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [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
Binding Affinity Annotations 
IDSourceBinding Affinity
4SN Binding MOAD:  4ZWY Ki: 10 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.173 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.156 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.178α = 90
b = 41.344β = 104.12
c = 71.816γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA165284

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-05
    Type: Initial release
  • Version 1.1: 2015-09-09
    Changes: Database references
  • Version 1.2: 2017-09-13
    Changes: Author supporting evidence, Database references, Derived calculations
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Refinement description