5V7A

E. coli dihydropteroate synthase complexed with an 8-mercaptoguanine derivative: 2-((2-amino-9-methyl-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)acetic acid

5V7A の概要

• エントリーDOI: 10.2210/pdb5v7a/pdb
• 関連するPDBエントリー: 5U0V 5U0W 5U0X 5U0Y 5U0Z 5U10 5U11 5U12 5U13 5U14 5V79
• 分子名称: Dihydropteroate synthase, [(2-amino-9-methyl-6-oxo-6,9-dihydro-1H-purin-8-yl)sulfanyl]acetic acid, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: e. coli, dhps, complex, pterin site, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Escherichia coli O6:H1 (strain CFT073 / ATCC 700928 / UPEC)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62138.42

構造登録者

Dennis, M.L.,Peat, T.S.,Swarbrick, J.D. (登録日: 2017-03-20, 公開日: 2017-12-06, 最終更新日: 2023-10-04)

主引用文献

Dennis, M.L.,Lee, M.D.,Harjani, J.R.,Ahmed, M.,DeBono, A.J.,Pitcher, N.P.,Wang, Z.C.,Chhabra, S.,Barlow, N.,Rahmani, R.,Cleary, B.,Dolezal, O.,Hattarki, M.,Aurelio, L.,Shonberg, J.,Graham, B.,Peat, T.S.,Baell, J.B.,Swarbrick, J.D.
8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase.
Chemistry, 24:1922-1930, 2018

PubMed Abstract: Dihydropteroate synthase (DHPS) is an enzyme of the folate biosynthesis pathway, which catalyzes the formation of 7,8-dihydropteroate (DHPt) from 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPPP) and para-aminobenzoic acid (pABA). DHPS is the long-standing target of the sulfonamide class of antibiotics that compete with pABA. In the wake of sulfa drug resistance, targeting the structurally rigid (and more conserved) pterin site has been proposed as an alternate strategy to inhibit DHPS in wild-type and sulfa drug resistant strains. Following the work on developing pterin-site inhibitors of the adjacent enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), we now present derivatives of 8-mercaptoguanine, a fragment that binds weakly within both enzymes, and quantify sub-μm binding using surface plasmon resonance (SPR) to Escherichia coli DHPS (EcDHPS). Eleven ligand-bound EcDHPS crystal structures delineate the structure-activity relationship observed providing a structural framework for the rational development of novel, substrate-envelope-compliant DHPS inhibitors.

PubMed: 29171692
DOI: 10.1002/chem.201704730

実験手法

X-RAY DIFFRACTION (2.35 Å)