1lrt

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spinqualitylabelsall models 1lrt, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF TERNARY COMPLEX OF TRITRICHOMONAS FOETUS INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE: STRUCTURAL CHARACTERIZATION OF NAD+ SITE IN MICROBIAL ENZYME

Overview

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the conversion of, IMP to XMP with the reduction of NAD(+), which is the rate-limiting step, in the biosynthesis of guanine nucleotides. IMPDH is a promising target, for chemotherapy. Microbial IMPDHs differ from mammalian enzymes in their, lower affinity for inhibitors such as mycophenolic acid (MPA) and, thiazole-4-carboxamide adenine dinucleotide (TAD). Part of this resistance, is determined by the coupling between nicotinamide and adenosine subsites, in the NAD(+) binding site that is postulated to involve an active site, flap. To understand the structural basis of the drug selectivity, we, solved the X-ray crystal structure of the catalytic core domain of, Tritrichomonas foetus IMPDH in complex with IMP and beta-methylene-TAD at, 2.2 A resolution. Unlike previous structures of this enzyme, the active, site loop is ordered in this complex, and the catalytic Cys319 is 3.6 A, from IMP, in the same plane as the hypoxanthine ring. The active site loop, forms hydrogen bonds to the carboxamide of beta-Me-TAD which suggests that, NAD(+) promotes the nucleophillic attack of Cys319 on IMP. The, interactions of the adenosine end of TAD are very different from those in, the human enzyme, suggesting the NAD(+) site may be an exploitable target, for the design of antimicrobial drugs. In addition, a new K(+) site is, observed at the subunit interface. This site is adjacent to beta-Me-TAD, consistent with the link between the K(+) activation and NAD(+). However, contrary to the coupling model, the flap does not cover the adenosine, subsite and remains largely disordered.

About this Structure

1LRT is a Single protein structure of sequence from Tritrichomonas foetus with BOG, K, IMP, TAD and TRS as ligands. Active as IMP dehydrogenase, with EC number 1.1.1.205 Full crystallographic information is available from OCA.

Reference

Crystal structure of a ternary complex of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase: NAD+ orients the active site loop for catalysis., Gan L, Petsko GA, Hedstrom L, Biochemistry. 2002 Nov 5;41(44):13309-17. PMID:12403633

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