4Q7W

Crystal structure of 1-hydroxy-6-methylpyridine-2(1H)-thione bound to human carbonic anhydrase II


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 

wwPDB Validation   3D Report Full Report


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
6MH
Query on 6MH

Download Ideal Coordinates CCD File 
C [auth A]1-hydroxy-6-methylpyridine-2(1H)-thione
C6 H7 N O S
KVLOEFKBTCCASR-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
E [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
NA
Query on NA

Download Ideal Coordinates CCD File 
F [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6MH Binding MOAD:  4Q7W Ki: 2.30e+6 (nM) from 1 assay(s)
BindingDB:  4Q7W Ki: 2.30e+6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.189α = 90
b = 41.418β = 104.5
c = 72.173γ = 90
Software Package:
Software NamePurpose
APEXdata collection
PHASERphasing
REFMACrefinement
APEXdata reduction

Structure Validation

View Full Validation Report



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