5tho

Crystal Structure of Mycobacterium Tuberculosis Proteasome in complex with N,C-capped Dipeptide Inhibitor PKS2205

spinqualitylabelsall models 5tho, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5tho is a 28 chain structure with sequence from Mycobacterium tuberculosis H37Ra. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.002Å Ligands: 7C7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PSA_MYCTA Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation. Publication Abstract from PubMed The 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Proteasome 3D structures

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