3TYZ

Crystal Structure of the Yersinia pestis Dihydropteroate synthetase with substrate transition state complex.

Summary for 3TYZ

• Entry DOI: 10.2210/pdb3tyz/pdb
• Related: 3TYU 3TZF 3TZN
• Descriptor: 7,8-dihydropteroate synthase, 2-amino-6-methylidene-6,7-dihydropteridin-4(3H)-one, PYROPHOSPHATE 2-, ... (6 entities in total)
• Functional Keywords: dihydropteroate synthase, transition state complex, paba, tim barrel, transferase-transferase substrate complex, transferase/transferase substrate
• Biological source: Yersinia pestis
• Total number of polymer chains: 2
• Total formula weight: 61664.58

Authors

Wu, Y. (deposition date: 2011-09-26, release date: 2012-03-14, Last modification date: 2024-02-28)

Primary citation

Yun, M.K.,Wu, Y.,Li, Z.,Zhao, Y.,Waddell, M.B.,Ferreira, A.M.,Lee, R.E.,Bashford, D.,White, S.W.
Catalysis and sulfa drug resistance in dihydropteroate synthase.
Science, 335:1110-1114, 2012

PubMed Abstract: The sulfonamide antibiotics inhibit dihydropteroate synthase (DHPS), a key enzyme in the folate pathway of bacteria and primitive eukaryotes. However, resistance mutations have severely compromised the usefulness of these drugs. We report structural, computational, and mutagenesis studies on the catalytic and resistance mechanisms of DHPS. By performing the enzyme-catalyzed reaction in crystalline DHPS, we have structurally characterized key intermediates along the reaction pathway. Results support an S(N)1 reaction mechanism via formation of a novel cationic pterin intermediate. We also show that two conserved loops generate a substructure during catalysis that creates a specific binding pocket for p-aminobenzoic acid, one of the two DHPS substrates. This substructure, together with the pterin-binding pocket, explains the roles of the conserved active-site residues and reveals how sulfonamide resistance arises.

PubMed: 22383850
DOI: 10.1126/science.1214641

Experimental method

X-RAY DIFFRACTION (2.07 Å)