6P9C

OXA-48 carbapanemase, doripenem complex

6P9C の概要

• エントリーDOI: 10.2210/pdb6p9c/pdb
• 分子名称: Beta-lactamase, (4R,5S)-5-[(2S,3R)-3-hydroxy-1-oxobutan-2-yl]-4-methyl-3-({(3S,5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl}sulfanyl)-4,5-dihydro-1H-pyrrole-2-carboxylic acid, Doripenem, ... (7 entities in total)
• 機能のキーワード: antibiotic resistance, beta-lactamase, carbapenemase, dorupenem complex, hydrolase-antibiotic complex, hydrolase/antibiotic
• 由来する生物種: Klebsiella pneumoniae
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62966.36

構造登録者

Smith, C.A.,Vakulenko, S.B. (登録日: 2019-06-10, 公開日: 2019-08-07, 最終更新日: 2024-10-23)

主引用文献

Smith, C.A.,Stewart, N.K.,Toth, M.,Vakulenko, S.B.
Structural Insights into the Mechanism of Carbapenemase Activity of the OXA-48 beta-Lactamase.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: Carbapenem-hydrolyzing class D carbapenemases (CHDLs) are enzymes that produce resistance to the last-resort carbapenem antibiotics, severely compromising the available therapeutic options for the treatment of life-threatening infections. A broad variety of CHDLs, including OXA-23, OXA-24/40, and OXA-58, circulate in , while the OXA-48 CHDL is predominant in Extensive structural studies of enzymes have provided important information regarding their interactions with carbapenems and significantly contributed to the understanding of the mechanism of their carbapenemase activity. However, the interactions between carbapenems and OXA-48 have not yet been elucidated. We determined the X-ray crystal structures of the acyl-enzyme complexes of OXA-48 with four carbapenems, imipenem, meropenem, ertapenem, and doripenem, and compared them with those of known carbapenem complexes of CHDLs. In the enzymes, acylation by carbapenems triggers significant displacement of one of two conserved hydrophobic surface residues, resulting in the formation of a channel for entry of the deacylating water into the active site. We show that such a channel preexists in apo-OXA-48 and that only minor displacement of the conserved hydrophobic surface residues occurs upon the formation of OXA-48 acyl-enzyme intermediates. We also demonstrate that the extensive hydrophobic interactions that occur between a conserved hydrophobic bridge of the CHDLs and the carbapenem tails are lost in OXA-48 in the absence of an equivalent bridge structure. These data highlight significant differences between the interactions of carbapenems with OXA-48 and those with enzymes and provide important insights into the mechanism of carbapenemase activity of the major CHDL, OXA-48.

PubMed: 31358584
DOI: 10.1128/AAC.01202-19

実験手法

X-RAY DIFFRACTION (1.9 Å)