4ptk

Publication Abstract from PubMed

Mg2+ -dependent, Li+ -sensitive phosphatases are a widely distributed family of enzymes with significant importance throughout the biological kingdom. Inositol monophosphatase (IMPase) is one of the important targets of Li+ -based therapeutics for manic depressive disorders. However, despite decades of intense research efforts, the precise mechanism of the Li+ -induced inhibition of IMPase remains obscured. In this study, we present the structural investigation of the Li+ binding site in staphylococcal IMPase-I (SaIMPase-I) using X-ray crystallography. Biochemical study evident common or overlapping binding site of Mg2+ and Li+ in the active site of SaIMPase-I. The crystal structure of SaIMPase-I ternary product complex shows a phosphate and three Mg2+ (namely Mg1, Mg2 and Mg3) in the active site. Since Li+ is virtually invisible in X-ray crystallography, the competitive displacement of Mg2+ ions from the SaIMPase-I ternary product complex as a function of an increasing LiCl concentration were employed to identify Li+ binding site. In this approach, the disappearing electron density of pre-occupied Mg2+ ions due to Li+ ions binding was traced and accordingly, the Mg2+ ion explicitly from the Mg2 binding site found to be replaced. Moreover, based on comparative detailed investigation of the phosphate orientation and coordination states of Mg2+ binding sites in enzyme-substrate and enzyme-product complexes, the inhibition mechanisms of Li+ and Mg2+ are proposed. This article is protected by copyright. All rights reserved. STRUCTURED DIGITAL ABSTRACT: SaIMPase-I and SaIMPase-I bind by x-ray crystallography (View interaction).

Structural Elucidation of the Binding Site and Mode of Inhibition of Li and Mg in Inositol Monophosphatase.,Dutta A, Bhattacharyya S, Dutta D, Das AK FEBS J. 2014 Sep 26. doi: 10.1111/febs.13070. PMID:25263816^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.