4Q81

Crystal structure of 1-hydroxy-4,6-dimethylpyridine-2(1H)-thione bound to human carbonic anhydrase II

Summary for 4Q81

• Entry DOI: 10.2210/pdb4q81/pdb
• Related: 3M1K 4Q7P 4Q7S 4Q7V 4Q7W 4Q83 4Q87 4Q8X 4Q8Y 4Q8Z 4Q90 4Q99 4Q9Y
• Descriptor: Carbonic anhydrase 2, ZINC ION, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: lyase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29909.52

Authors

Martin, D.P.,Cohen, S.M. (deposition date: 2014-04-25, release date: 2015-03-11, Last modification date: 2023-09-20)

Primary citation

Martin, D.P.,Blachly, P.G.,McCammon, J.A.,Cohen, S.M.
Exploring the influence of the protein environment on metal-binding pharmacophores.
J.Med.Chem., 57:7126-7135, 2014

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.

PubMed: 25116076
DOI: 10.1021/jm500984b

Experimental method

X-RAY DIFFRACTION (1.55 Å)