5ISP

Staphylococcus aureus F98Y Dihydrofolate Reductase mutant complexed with beta-NADPH and 3'-(3-(2,4-diamino-6-ethylpyrimidin-5-yl)prop-2-yn-1-yl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid (UCP1106)

5ISP の概要

• エントリーDOI: 10.2210/pdb5isp/pdb
• 関連するPDBエントリー: 5HF0 5HF2 5ISQ 5IST
• 分子名称: Dihydrofolate reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-[3-[3-[2,4-bis(azanyl)-6-ethyl-pyrimidin-5-yl]prop-2-ynyl]-4-methoxy-phenyl]benzoic acid, ... (5 entities in total)
• 機能のキーワード: oxidoreductase, dihydrofolate reductase, nadph, zwitterion, antibiotics
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19649.92

構造登録者

Anderson, A.C.,Reeve, S.M. (登録日: 2016-03-15, 公開日: 2017-06-28, 最終更新日: 2024-03-06)

主引用文献

Reeve, S.M.,Scocchera, E.,Ferreira, J.J.,G-Dayanandan, N.,Keshipeddy, S.,Wright, D.L.,Anderson, A.C.
Charged Propargyl-Linked Antifolates Reveal Mechanisms of Antifolate Resistance and Inhibit Trimethoprim-Resistant MRSA Strains Possessing Clinically Relevant Mutations.
J. Med. Chem., 59:6493-6500, 2016

PubMed Abstract: Drug-resistant enzymes must balance catalytic function with inhibitor destabilization to provide a fitness advantage. This sensitive balance, often involving very subtle structural changes, must be achieved through a selection process involving a minimal number of eligible point mutations. As part of a program to design propargyl-linked antifolates (PLAs) against trimethoprim-resistant dihydrofolate reductase (DHFR) from Staphylococcus aureus, we have conducted a thorough study of several clinically observed chromosomal mutations in the enzyme at the cellular, biochemical, and structural levels. Through this work, we have identified a promising lead series that displays significantly greater activity against these mutant enzymes and strains than TMP. The best inhibitors have enzyme inhibition and MIC values near or below that of trimethoprim against wild-type S. aureus. Moreover, these studies employ a series of crystal structures of several mutant enzymes bound to the same inhibitor; analysis of the structures reveals a more detailed molecular understanding of drug resistance in this important enzyme.

PubMed: 27308944
DOI: 10.1021/acs.jmedchem.6b00688

実験手法

X-RAY DIFFRACTION (1.84 Å)