4b2x
Pseudomonas aeruginosa RmlA in complex with allosteric inhibitorPseudomonas aeruginosa RmlA in complex with allosteric inhibitor
Structural highlights
FunctionQ9HU22_PSEAE Catalyzes the formation of dTDP-glucose, from dTTP and glucose 1-phosphate, as well as its pyrophosphorolysis (By similarity).[RuleBase:RU003706] Publication Abstract from PubMedGlucose-1-phosphate thymidylyltransferase (RmlA) catalyzes the condensation of glucose-1-phosphate (G1P) with deoxy-thymidine tri-phosphate (dTTP) to yield dTDP-L-rhamnose and pyrophosphate. This is the first step in the L-rhamnose biosynthetic pathway. L-rhamnose is an important component of the cell wall of many microorganisms, including Mycobacterium tuberculosis and Pseudomonas aeruginosa. Here we describe the first nanomolar inhibitors of P. aeruginosa RmlA. These thymine analogs were identified by high-throughput screening and subsequently optimized by a combination of protein crystallography, in silico screening and synthetic chemistry. Some of the inhibitors show inhibitory activity against M. tuberculosis. The inhibitors do not bind at the active site of RmlA but bind at a second site remote from the active site. Despite this, the compounds act as competitive inhibitors of G1P but with high cooperativity. This novel behavior was probed by structural analysis which suggests that the inhibitors work by preventing RmlA from undergoing the conformational change key to its ordered bi-bi mechanism. Allosteric Competitive Inhibitors of the Glucose-1-Phosphate Thymidylyltransferase (RmlA) from Pseudomonas aeruginosa.,Alphey MS, Pirrie L, Torrie LS, Boulkeroura WA, Gardiner M, Sarkar A, Maringer M, Oehlmann W, Brenk R, Scherman MS, McNeil M, Rejzek M, Field RA, Singh M, Gray D, Westwood NJ, Naismith JH ACS Chem Biol. 2012 Nov 8. PMID:23138692[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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