7zxs

Crystal structure of DPP9 in complex with a 4-oxo-b-lactam based inhibitor, A295

spinqualitylabelsall models 7zxs, resolution 1.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7zxs is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CSO, EDO, KBO, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DPP9_HUMAN Idiopathic pulmonary fibrosis. Function DPP9_HUMAN Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. Publication Abstract from PubMed Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-beta-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date. Chemoproteomics-Enabled Identification of 4-Oxo-beta-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.,Carvalho LAR, Ross B, Fehr L, Bolgi O, Wohrle S, Lum KM, Podlesainski D, Vieira AC, Kiefersauer R, Felix R, Rodrigues T, Lucas SD, Gross O, Geiss-Friedlander R, Cravatt BF, Huber R, Kaiser M, Moreira R Angew Chem Int Ed Engl. 2022 Sep 11. doi: 10.1002/anie.202210498. PMID:36089535 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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