2QP6

The crystal structure of the complex of hcaII with a bioreductive antitumor derivative


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.192 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Carbonic Anhydrase Inhibitors: Bioreductive Nitro-Containing Sulfonamides with Selectivity for Targeting the Tumor Associated Isoforms IX and XII.

D'Ambrosio, K.Vitale, R.M.Dogne, J.M.Masereel, B.Innocenti, A.Scozzafava, A.De Simone, G.Supuran, C.T.

(2008) J Med Chem 51: 3230-3237

  • DOI: https://doi.org/10.1021/jm800121c
  • Primary Citation of Related Structures:  
    2QP6

  • PubMed Abstract: 

    2-Substituted-5-nitro-benzenesulfonamides incorporating a large variety of secondary/tertiary amines were explored as inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), with the aim of designing bioreductive inhibitors targeting the hypoxia overexpressed, tumor-associated isozymes. The compounds were ineffective inhibitors of the cytosolic isoform I, showed a better inhibition of the physiologically relevant CA II (KIs of 8.8-4975 nM), and strongly inhibited the tumor-associated CA IX and XII (KIs of 5.4-653 nM). Some of these compounds showed excellent selectivity ratios for the inhibition of the tumor-associated isozymes over the cytosolic ones (in the range of 10-1395). The X-ray crystal structure of the adduct of hCA II with the lead molecule 2-chloro-5-nitro-benzenesulfonamide as well as molecular modeling studies for interaction with hCA IX afforded a better understanding of factors governing the discrimination of the two isoforms for this type of bioreductive compound targeting specifically hypoxic tumors.


  • Organizational Affiliation

    Istituto di Biostrutture e Bioimmagini-CNR, Napoli, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2259Homo sapiensMutation(s): 0 
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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MBO
Query on MBO

Download Ideal Coordinates CCD File 
E [auth A]MERCURIBENZOIC ACID
C7 H5 Hg O2
FVFZSVRSDNUCGG-UHFFFAOYSA-N
MB1
Query on MB1

Download Ideal Coordinates CCD File 
F [auth A]2-chloro-5-nitrobenzenesulfonamide
C6 H5 Cl N2 O4 S
ZAJALNCZCSSGJC-UHFFFAOYSA-N
HG
Query on HG

Download Ideal Coordinates CCD File 
D [auth A]MERCURY (II) ION
Hg
BQPIGGFYSBELGY-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
MB1 PDBBind:  2QP6 Ki: 208 (nM) from 1 assay(s)
Binding MOAD:  2QP6 Ki: 208 (nM) from 1 assay(s)
CL BindingDB:  2QP6 Ki: min: 2.00e+8, max: 2.00e+8 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.192 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.069α = 90
b = 41.238β = 104.2
c = 71.829γ = 90
Software Package:
Software NamePurpose
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-06-03
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description