4FN2

Crystal structure of a SMT fusion Peptidyl-prolyl cis-trans isomerase with surface mutation D44G from Burkholderia pseudomallei complexed with CJ37

4FN2 の概要

• エントリーDOI: 10.2210/pdb4fn2/pdb
• 関連するPDBエントリー: 2KEO 2KO7 2L2S 3UF8 3UQA 3UQB 3VAW 4DZ2 4DZ3
• 分子名称: Ubiquitin-like protein SMT3, Peptidyl-prolyl cis-trans isomerase, ethyl (2S)-1-(benzylsulfonyl)piperidine-2-carboxylate (3 entities in total)
• 機能のキーワード: ssgcid, structural genomics, seattle structural genomics center for infectious disease, isomerase, protein binding
• 由来する生物種: Saccharomyces cerevisiae; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 46510.38

構造登録者

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (登録日: 2012-06-19, 公開日: 2012-08-01, 最終更新日: 2023-09-13)

主引用文献

Begley, D.W.,Fox, D.,Jenner, D.,Juli, C.,Pierce, P.G.,Abendroth, J.,Muruthi, M.,Safford, K.,Anderson, V.,Atkins, K.,Barnes, S.R.,Moen, S.O.,Raymond, A.C.,Stacy, R.,Myler, P.J.,Staker, B.L.,Harmer, N.J.,Norville, I.H.,Holzgrabe, U.,Sarkar-Tyson, M.,Edwards, T.E.,Lorimer, D.D.
A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins.
Antimicrob.Agents Chemother., 58:1458-1467, 2014

PubMed Abstract: Macrophage infectivity potentiators (Mips) are immunophilin proteins and essential virulence factors for a range of pathogenic organisms. We applied a structural biology approach to characterize a Mip from Burkholderia pseudomallei (BpML1), the causative agent of melioidosis. Crystal structure and nuclear magnetic resonance analyses of BpML1 in complex with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. This scaffold possesses inhibitory potency for BpML1 without the immunosuppressive components of related macrocyclic agents. Biophysical characterization of a compound series with this scaffold allowed binding site specificity in solution and potency determinations for rank ordering the set. The best compounds in this series possessed a low-micromolar affinity for BpML1, bound at the site of enzymatic activity, and inhibited a panel of homologous Mip proteins from other pathogenic bacteria, without demonstrating toxicity in human macrophages. Importantly, the in vitro activity of BpML1 was reduced by these compounds, leading to decreased macrophage infectivity and intracellular growth of Burkholderia pseudomallei. These compounds offer the potential for activity against a new class of antimicrobial targets and present the utility of a structure-based approach for novel antimicrobial drug discovery.

PubMed: 24366729
DOI: 10.1128/AAC.01875-13

実験手法

X-RAY DIFFRACTION (1.95 Å)