1EYE

1.7 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTEROATE SYNTHASE (DHPS) FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH 6-HYDROXYMETHYLPTERIN MONOPHOSPHATE

Summary for 1EYE

• Entry DOI: 10.2210/pdb1eye/pdb
• Related: 1ad1 1ad4 1aj0 1aj2 1ajz
• Descriptor: DIHYDROPTEROATE SYNTHASE I, MAGNESIUM ION, PTERIN-6-YL-METHYL-MONOPHOSPHATE, ... (4 entities in total)
• Functional Keywords: alpha-beta barrel, transferase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 1
• Total formula weight: 29170.36

Authors

Baca, A.M.,Sirawaraporn, R.,Turley, S.,Sirawaraporn, W.,Hol, W.G.J. (deposition date: 2000-05-05, release date: 2000-10-11, Last modification date: 2024-03-13)

Primary citation

Baca, A.M.,Sirawaraporn, R.,Turley, S.,Sirawaraporn, W.,Hol, W.G.
Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action.
J.Mol.Biol., 302:1193-1212, 2000

PubMed Abstract: 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.

PubMed: 11007651
DOI: 10.1006/jmbi.2000.4094

Experimental method

X-RAY DIFFRACTION (1.7 Å)