1lrt
From Proteopedia
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'''CRYSTAL STRUCTURE OF TERNARY COMPLEX OF TRITRICHOMONAS FOETUS INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE: STRUCTURAL CHARACTERIZATION OF NAD+ SITE IN MICROBIAL ENZYME''' | '''CRYSTAL STRUCTURE OF TERNARY COMPLEX OF TRITRICHOMONAS FOETUS INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE: STRUCTURAL CHARACTERIZATION OF NAD+ SITE IN MICROBIAL ENZYME''' | ||
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[[Category: Hedstrom, L.]] | [[Category: Hedstrom, L.]] | ||
[[Category: Petsko, G A.]] | [[Category: Petsko, G A.]] | ||
| - | [[Category: | + | [[Category: Alpha-beta barrel]] |
| - | [[Category: | + | [[Category: Flap]] |
| - | [[Category: | + | [[Category: Flexible loop]] |
| - | [[Category: | + | [[Category: Ternary complex]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 00:13:24 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 21:13, 2 May 2008
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. 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 Page seeded by OCA on Sat May 3 00:13:24 2008
