4OR7

Klebsiella pneumoniae dihydrofolate reductase complexed with NADPH and 6-ethyl-5-{3-[3-(pyrimidin-5-yl)phenyl]prop-1-yn-1-yl}pyrimidine-2,4-diamine

4OR7 の概要

• エントリーDOI: 10.2210/pdb4or7/pdb
• 関連するPDBエントリー: 4OSG
• 分子名称: Dihydrofolate reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-ethyl-5-{3-[3-(pyrimidin-5-yl)phenyl]prop-1-yn-1-yl}pyrimidine-2,4-diamine, ... (4 entities in total)
• 機能のキーワード: 5, 6, 7, 8-tetrahydrofolate; 7, 8-dihydrofolate, hydride shift, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Klebsiella pneumoniae CG43
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19886.94

構造登録者

Lamb, K.M.,Anderson, A.C. (登録日: 2014-02-11, 公開日: 2014-12-03, 最終更新日: 2024-02-28)

主引用文献

Lamb, K.M.,Lombardo, M.N.,Alverson, J.,Priestley, N.D.,Wright, D.L.,Anderson, A.C.
Crystal Structures of Klebsiella pneumoniae Dihydrofolate Reductase Bound to Propargyl-Linked Antifolates Reveal Features for Potency and Selectivity.
Antimicrob.Agents Chemother., 58:7484-7491, 2014

PubMed Abstract: Resistance to the antibacterial antifolate trimethoprim (TMP) is increasing in members of the family Enterobacteriaceae, driving the design of next-generation antifolates effective against these Gram-negative pathogens. The propargyl-linked antifolates are potent inhibitors of dihydrofolate reductases (DHFR) from several TMP-sensitive and -resistant species, including Klebsiella pneumoniae. Recently, we have determined that these antifolates inhibit the growth of strains of K. pneumoniae, some with MIC values of 1 μg/ml. In order to further the design of potent and selective antifolates against members of the Enterobacteriaceae, we determined the first crystal structures of K. pneumoniae DHFR bound to two of the propargyl-linked antifolates. These structures highlight that interactions with Leu 28, Ile 50, Ile 94, and Leu 54 are necessary for potency; comparison with structures of human DHFR bound to the same inhibitors reveal differences in residues (N64E, P61G, F31L, and V115I) and loop conformations (residues 49 to 53) that may be exploited for selectivity.

PubMed: 25288083
DOI: 10.1128/AAC.03555-14

実験手法

X-RAY DIFFRACTION (1.76 Å)