Metalloprotein–Inhibitor Binding: Human Carbonic Anhydrase II as a Model for Probing Metal–Ligand Interactions in a Metalloprotein Active Site
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States
Inorg. Chem., 2013, 52 (21), pp 12207–12215
DOI: 10.1021/ic400295f
Publication Date (Web): May 24, 2013
Copyright © 2013 American Chemical Society
*E-mail: scohen@ucsd.edu.
This article is part of the Metals in Medicine and Health special issue.
Synopsis
Human carbonic anhydrase II (hCAII), a zinc(II)-dependent hydrolase, has been widely studied to understand ligand−protein binding such as hydrogen-bonding and hydrophobic interactions. This report expands the use of hCAII as a model system by examining how ligand binding is effected by mutations of residues within the zinc(II)-ion coordination sphere. In this way, we can begin to understand how metal-binding group selectivity and affinity is perturbed by the composition of the ligating active-site residues.
Abstract
An ever-increasing number of metalloproteins are being discovered that play essential roles in physiological processes. Inhibitors of these proteins have significant potential for the treatment of human disease, but clinical success of these compounds has been limited. Herein, zinc(II)-dependent metalloprotein inhibitors in clinical use are reviewed, and the potential for using novel metal-binding groups (MBGs) in the design of these inhibitors is discussed. By using human carbonic anhydrase II as a model system, the nuances of MBG–metal interactions in the context of a protein environment can be probed. Understanding how metal coordination influences inhibitor binding may help in the design of new therapeutics targeting metalloproteins.
Supporting Information
Experimental details, refinement data, structures of compounds, and activity inhibition. This material is available free of charge via the Internet at http://pubs.acs.org.
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