4GGQ

Crystal structure of a SMT fusion Peptidyl-prolyl cis-trans isomerase from Burkholderia pseudomallei complexed with CJ40

Summary for 4GGQ

• Entry DOI: 10.2210/pdb4ggq/pdb
• Related: 2KEO 2KO7 2L2S 3UF8 3UQA 3UQB 3VAW 4DZ2 4DZ3 4FN2 4G50
• Descriptor: Ubiquitin-like protein SMT3, Peptidyl-prolyl cis-trans isomerase, CALCIUM ION, 3-(3,4,5-trimethoxyphenyl)propyl (2S)-1-(benzylsulfonyl)piperidine-2-carboxylate, ... (5 entities in total)
• Functional Keywords: ssgcid, isomerase, structural genomics, seattle structural genomics center for infectious disease, protein binding
• Biological source: Saccharomyces cerevisiae; More
• Total number of polymer chains: 4
• Total formula weight: 94159.98

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2012-08-07, release date: 2012-08-15, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.95 Å)