5oeq

Mycobacterium tuberculosis DprE1 in complex with inhibitor TCA020

spinqualitylabelsall models 5oeq, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5oeq is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FAD, IMD, P95 Related: 4kw5, 5oel, 5oep Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB. Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes.,Liu R, Lyu X, Batt SM, Hsu MH, Harbut MB, Vilcheze C, Cheng B, Ajayi K, Yang B, Yang Y, Guo H, Lin C, Gan F, Wang C, Franzblau SG, Jacobs WR Jr, Besra GS, Johnson EF, Petrassi M, Chatterjee AK, Futterer K, Wang F Angew Chem Int Ed Engl. 2017 Aug 16. doi: 10.1002/anie.201707324. PMID:28815830 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA