4Q8Y

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

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.162 

wwPDB Validation 3D Report Full Report


This is version 1.0 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: 10.1021/jm500984b
  • Primary Citation of Related Structures:  

  • 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 ...

    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: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Carbonic anhydrase 2
A
260Homo sapiensMutation(s): 0 
Gene Names: CA2
EC: 4.2.1.1
Find proteins for P00918 (Homo sapiens)
Go to Gene View: CA2
Go to UniProtKB:  P00918
Small Molecules
Ligands 3 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
MBO
Query on MBO
Download SDF File 
Download CCD File 
A
MERCURIBENZOIC ACID
C7 H5 Hg O2
FVFZSVRSDNUCGG-UHFFFAOYSA-N
 Ligand Interaction
HQT
Query on HQT
Download SDF File 
Download CCD File 
A
2-hydroxyisoquinoline-1(2H)-thione
C9 H7 N O S
RTPXYUZLLYULJQ-UHFFFAOYSA-N
 Ligand Interaction
ZN
Query on ZN
Download SDF File 
Download CCD File 
A
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
 Ligand Interaction
External Ligand Annotations 
IDBinding Affinity (Sequence Identity %)
HQTKi: 2300000 nM (100) BINDINGDB
HQTKi: 2300000 nM BINDINGMOAD
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.162 
  • Space Group: P 1 21 1
Unit Cell:
Length (Å)Angle (°)
a = 42.089α = 90.00
b = 41.383β = 104.22
c = 71.767γ = 90.00
Software Package:
Software NamePurpose
APEXdata collection
PHASERphasing
REFMACrefinement
APEXdata reduction

Structure Validation

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Entry History 

Deposition Data

Revision History 

  • Version 1.0: 2015-03-11
    Type: Initial release