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Hydrolysis of diadenosine polyphosphates. Exploration of an additional role of Mycobacterium smegmatis MutT1

Arif, SM and Varshney, U and Vijayan, M (2017) Hydrolysis of diadenosine polyphosphates. Exploration of an additional role of Mycobacterium smegmatis MutT1. In: JOURNAL OF STRUCTURAL BIOLOGY, 199 (3). pp. 165-176.

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Official URL: http://doi.org/10.1016/j.jsb.2017.07.002

Abstract

Diadenosine polyphosphates (Ap(n)A, n = 2-6), particularly Ap(4)A, are involved in several important physiological processes. The substantial sequence identity of the Nudix hydrolase domain (domain 1) of Mycobacterium smegmatis MutT1 (MsMutT1) with a known Ap(4)A hydrolase suggested that MsMutTl could also hydrolyse diadenosine polyphosphates. Biochemical experiments yielded results in conformity with this suggestion, with Ap(4)A as the best among the substrates. ATP is a product in all experiments; small amounts of ADP were also observed in the experiments involving Ap(4)A and Ap(6)A. Hydrolysis was inhibited by fluoride ions in all cases. The mechanism of action and its inhibition in relation to ApnA were explored through the X-ray analysis of the crystals of the MsMutTl complexes with Ap(5)A; Ap(5)A and MnCl2; Ap(4)A; ATP; and ATP.NaF.MgCl2. The aggregation pattern of molecules in the first four crystals is similar to that found in a majority of MsMutT1-NTP crystals. Substrate molecules occupy the primary binding site and ATP occupies a site at an intermolecular interface, in the first two. ATP occupies both the sites in the third and fourth crystal. The protein-ligand interactions observed in these crystal structures lead to an explanation of the molecular mechanism of hydrolysis of Ap(n)A by MsMutTl. The fifth crystal exhibits a new packing arrangement. The structure of the complex provides an explanation for the fluoride inhibition of the activity of the enzyme. It would thus appear that MutT1 has a major role involving the hydrolysis of diadenosine polyphosphates, which could be elucidated at the molecular level. (C) 2017 Elsevier Inc. All rights reserved.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the ACADEMIC PRESS INC ELSEVIER SCIENCE, 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Depositing User: Id for Latest eprints
Date Deposited: 21 Oct 2017 06:17
Last Modified: 21 Feb 2019 10:36
URI: http://eprints.iisc.ac.in/id/eprint/58066

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