4Q99

Crystal structure of 2-mercapto-4-methylphenol bound to human carbonic anhydrase II


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.165 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Exploring the influence of the protein environment on metal-binding pharmacophores.

Martin, D.P.Blachly, P.G.McCammon, J.A.Cohen, S.M.

(2014) J Med Chem 57: 7126-7135

  • DOI: https://doi.org/10.1021/jm500984b
  • Primary Citation of Related Structures:  
    4Q7P, 4Q7S, 4Q7V, 4Q7W, 4Q81, 4Q83, 4Q87, 4Q8X, 4Q8Y, 4Q8Z, 4Q90, 4Q99, 4Q9Y

  • PubMed Abstract: 

    The binding of a series of metal-binding pharmacophores (MBPs) related to the ligand 1-hydroxypyridine-2-(1H)-thione (1,2-HOPTO) in the active site of human carbonic anhydrase II (hCAII) has been investigated. The presence and/or position of a single methyl substituent drastically alters inhibitor potency and can result in coordination modes not observed in small-molecule model complexes. It is shown that this unexpected binding mode is the result of a steric clash between the methyl group and a highly ordered water network in the active site that is further stabilized by the formation of a hydrogen bond and favorable hydrophobic contacts. The affinity of MBPs is dependent on a large number of factors including donor atom identity, orientation, electrostatics, and van der Waals interactions. These results suggest that metal coordination by metalloenzyme inhibitors is a malleable interaction and that it is thus more appropriate to consider the metal-binding motif of these inhibitors as a pharmacophore rather than a "chelator". The rational design of inhibitors targeting metalloenzymes will benefit greatly from a deeper understanding of the interplay between the variety of forces governing the binding of MBPs to active site metal ions.


  • Organizational Affiliation

    Departments of Chemistry and Biochemistry, ‡Pharmacology, and §Howard Hughes Medical Institute, University of California, San Diego , 9500 Gilman Drive, MC 0358, La Jolla, California 92093, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2260Homo 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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MBO
Query on MBO

Download Ideal Coordinates CCD File 
D [auth A]MERCURIBENZOIC ACID
C7 H5 Hg O2
FVFZSVRSDNUCGG-UHFFFAOYSA-N
HT4
Query on HT4

Download Ideal Coordinates CCD File 
C [auth A]4-methyl-2-sulfanylphenol
C7 H8 O S
GWMWXFGQYATKBA-UHFFFAOYSA-N
GOL
Query on GOL

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

Download Ideal Coordinates CCD File 
F [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-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
HT4 Binding MOAD:  4Q99 Ki: 520 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.165 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.115α = 90
b = 41.256β = 104.17
c = 71.824γ = 90
Software Package:
Software NamePurpose
APEXdata collection
PHASERphasing
REFMACrefinement
APEXdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-03-11
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description