The active site of a zinc-dependent metalloproteinase influences the computed pK(a) of ligands coordinated to the catalytic zinc ion |
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Authors: | Cross Jason B Duca José S Kaminski James J Madison Vincent S |
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Institution: | Contribution from the Department of Structural Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. |
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Abstract: | TNF-alpha converting enzyme (TACE) is a multidomain, membrane-anchored protein that includes a Zn-dependent protease domain. It releases the soluble form of cytokine tumor necrosis factor-alpha (TNF-alpha) from its membrane-bound precursor. TACE is a metalloprotease containing a catalytic glutamic acid, Glu-406, and a Zn(2+) ion ligated to three imidazoles. The protonation states of the active site glutamic acid and inhibitors are important factors in understanding the potency of inhibitors with acidic zinc-ligating groups such as hydroxamic and carboxylic acids. Density functional methods were utilized to compute pK(a) values using a model of the catalytic site of TACE and to predict a concomitant mechanism of binding, consistent with lowering the pK(a) of the bound ligand and raising the pK(a) of the active site Glu-406. Weak acids, such as hydroxamic acids, bind in their neutral form and then transfer an acidic proton to Glu-406. Stronger acids, such as carboxylic acids, bind in their anionic form and require preprotonation of Glu-406. Similar binding events would be expected for other zinc-dependent proteases. |
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