5trr
Structure of Mycobacterium tuberculosis proteasome in complex with N,C-capped dipeptide PKS2169Structure of Mycobacterium tuberculosis proteasome in complex with N,C-capped dipeptide PKS2169
Structural highlights
Function[PSA_MYCTA] Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation. [PSB_MYCTA] Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation. Publication Abstract from PubMedThe Mycobacterium tuberculosis (Mtb) 20S proteasome is vital for the pathogen to survive under nitrosative stress in vitro and to persist in mice. To qualify for drug development, inhibitors targeting Mtb 20S must spare both the human constitutive proteasome (c-20S) and immunoproteasome (i-20S). We recently reported members of a family of noncovalently binding dipeptide proteasome inhibitors that are highly potent and selective for Mtb 20S over human c-20S and i-20S. To understand the structural basis of their potency and selectivity, we have studied the structure-activity relationship of six derivatives and solved their cocrystal structures with Mtb 20S. The dipeptide inhibitors form an antiparallel beta-strand with the active site beta-strands. Selectivity is conferred by several features of Mtb 20S relative to its mouse counterparts, including a larger S1 pocket, additional hydrogen bonds in the S3 pocket, and hydrophobic interactions in the S4 pocket. Serine-20 and glutamine-22 of Mtb 20S interact with the dipeptides and confer Mtb-specific inhibition over c-20S and i-20S. The Mtb 20S and mammalian i-20S have a serine-27 that interacts strongly with the dipeptides, potentially explaining the higher inhibitory activity of the dipeptides toward i-20S over c-20S. This detailed structural knowledge will aid in optimizing the dipeptides as anti-tuberculosis drugs. Structural Basis for the Species-Selective Binding of N,C-Capped Dipeptides to the Mycobacterium tuberculosis Proteasome.,Hsu HC, Singh PK, Fan H, Wang R, Sukenick G, Nathan C, Lin G, Li H Biochemistry. 2017 Jan 10;56(1):324-333. doi: 10.1021/acs.biochem.6b01107. Epub, 2016 Dec 27. PMID:27976853[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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