9b06

Mycolicibacterium smegmatis ClpS with LeuThr dipeptide and Mg2+

spinqualitylabelsall models 9b06, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9b06 is a 2 chain structure with sequence from Mycolicibacterium smegmatis MC2 155. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: LCZ, MG, NI, THR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0R1X7_MYCS2 Involved in the modulation of the specificity of the ClpAP-mediated ATP-dependent protein degradation.[HAMAP-Rule:MF_00302] Publication Abstract from PubMed Drug-resistant tuberculosis infections are a major threat to global public health. The essential mycobacterial ClpC1P1P2 protease has received attention as a prospective target for novel antibacterial therapeutics. However, efforts to probe its function in cells are constrained by our limited knowledge of its physiological proteolytic repertoire. Here, we interrogate the role of mycobacterial ClpS in directing N-degron pathway proteolysis by ClpC1P1P2 in Mycolicibacterium smegmatis. Binding assays demonstrate that mycobacterial ClpS binds canonical primary destabilizing residues (Leu, Phe, Tyr, Trp) with moderate affinity. N-degron binding restricts the conformational flexibility of a loop adjacent to the ClpS N-degron binding pocket and strengthens ClpS*ClpC1 binding affinity ~30-fold, providing a mechanism for cells to prioritize N-degron proteolysis when substrates are abundant. Proteolytic reporter assays in M. smegmatis confirm degradation of substrates bearing primary N-degrons, but suggest that secondary N-degrons are absent in mycobacteria. This work expands our understanding of the mycobacterial N-degron pathway and identifies ClpS as a critical component for substrate specificity, providing insights that may support the development of improved Clp protease inhibitors. ClpS Directs Degradation of N-Degron Substrates With Primary Destabilizing Residues in Mycolicibacterium smegmatis.,Presloid CJ, Jiang J, Kandel P, Anderson HR, Beardslee PC, Swayne TM, Schmitz KR Mol Microbiol. 2024 Dec 3. doi: 10.1111/mmi.15334. PMID:39626090 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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