6OCZ

Crystal Structure of Mycobacterium tuberculosis Proteasome in Complex with Phenylimidazole-based Inhibitor A86

Summary for 6OCZ

• Entry DOI: 10.2210/pdb6ocz/pdb
• Descriptor: Proteasome subunit alpha, Proteasome subunit beta, DIMETHYLFORMAMIDE, ... (6 entities in total)
• Functional Keywords: mycobacterium tuberculosis, proteasome inhibitor, phenylimidazole, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); More
• Total number of polymer chains: 28
• Total formula weight: 717940.80

Authors

Hsu, H.C.,Li, H. (deposition date: 2019-03-25, release date: 2019-10-09, Last modification date: 2024-03-13)

Primary citation

Zhan, W.,Hsu, H.C.,Morgan, T.,Ouellette, T.,Burns-Huang, K.,Hara, R.,Wright, A.G.,Imaeda, T.,Okamoto, R.,Sato, K.,Michino, M.,Ramjee, M.,Aso, K.,Meinke, P.T.,Foley, M.,Nathan, C.F.,Li, H.,Lin, G.
Selective Phenylimidazole-Based Inhibitors of theMycobacterium tuberculosisProteasome.
J.Med.Chem., 62:9246-9253, 2019

PubMed Abstract: Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) renders nonreplicating Mtb susceptible to reactive nitrogen species in vitro and unable to survive in the lungs of mice, validating the Mtb proteasome as a promising target for anti-Mtb agents. Using a structure-guided and flow chemistry-enabled study of structure-activity relationships, we developed phenylimidazole-based peptidomimetics that are highly potent for Mtb20S. X-ray structures of selected compounds with Mtb20S shed light on their selectivity for mycobacterial over human proteasomes.

PubMed: 31560200
DOI: 10.1021/acs.jmedchem.9b01187

Experimental method

X-RAY DIFFRACTION (2.65 Å)