1eye
From Proteopedia
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1.7 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTEROATE SYNTHASE (DHPS) FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH 6-HYDROXYMETHYLPTERIN MONOPHOSPHATE
Overview
The enzyme 7,8-dihydropteroate synthase (DHPS) catalyzes the condensation, of para-aminobenzoic acid (pABA) with 6-hydroxymethyl-7, 8-dihydropterin-pyrophosphate to form 7,8-dihydropteroate and, pyrophosphate. DHPS is essential for the de novo synthesis of folate in, prokaryotes, lower eukaryotes, and in plants, but is absent in mammals., Inhibition of this enzyme's activity by sulfonamide and sulfone drugs, depletes the folate pool, resulting in growth inhibition and cell death., Here, we report the 1.7 A resolution crystal structure of the binary, complex of 6-hydroxymethylpterin monophosphate (PtP) with DHPS from, Mycobacterium tuberculosis (Mtb), a pathogen responsible for the death of, millions of human beings each year. Comparison to other DHPS structures, reveals that the M. tuberculosis DHPS structure is in a unique, conformation in which loop 1 closes over the active site. The Mtb DHPS, structure hints at a mechanism in which both loops 1 and 2 play important, roles in catalysis by shielding the active site from bulk solvent and, allowing pyrophosphoryl transfer to occur. A binding mode for pABA, sulfonamides and sulfones is suggested based on: (i) the new conformation, of the closed loop 1; (ii) the distribution of dapsone and sulfonamide, resistance mutations; (iii) the observed direction of the bond between the, 6-methyl carbon atom and the bridging oxygen atom to the alpha-phosphate, group in the Mtb DHPS:PtP binary complex; and (iv) the conformation of, loop 2 in the Escherichia coli DHPS structure. Finally, the Mtb DHPS, structure reveals a highly conserved pterin binding pocket that may be, exploited for the design of novel antimycobacterial agents.
About this Structure
1EYE is a Single protein structure of sequence from Mycobacterium tuberculosis with MG and PMM as ligands. Active as Dihydropteroate synthase, with EC number 2.5.1.15 Full crystallographic information is available from OCA.
Reference
Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action., Baca AM, Sirawaraporn R, Turley S, Sirawaraporn W, Hol WG, J Mol Biol. 2000 Oct 6;302(5):1193-212. PMID:11007651
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