9cza

Crystal structure of integrin avb6 headpiece in complex with compound 18

spinqualitylabelsall models 9cza, resolution 2.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9cza is a 4 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.49Å Ligands: A1A6B, ACT, BMA, CA, GOL, MAN, MG, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ITAV_HUMAN The alpha-V integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. Publication Abstract from PubMed Inhibition of integrin alphavbeta6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin alphaIIbbeta3 with alphav integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of alphavbeta6. Crystal structures of these compounds bound to alphavbeta6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations. Optimization of PK parameters including permeability, bioavailability, clearance, and half-life resulted in the discovery of development candidate MORF-627, a highly selective inhibitor of alphavbeta6 that stabilizes the bent-closed conformation and has good oral PK. Unfortunately, the compound showed toxicity in a 28-day NHP safety study, precluding further development. Nevertheless, MORF-627 is a useful tool compound for studying the biology of integrin alphavbeta6. The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin alphavbeta6 Inhibitor for Fibrosis.,Harrison BA, Dowling JE, Bursavich MG, Troast DM, Chong KM, Hahn KN, Zhong C, Mulvihill KM, Nguyen H, Monroy MF, Qiao Q, Sosa B, Mostafavi S, Smukste I, Lee D, Cappellucci L, Konopka EH, Nowakowski P, Stawski L, Senices M, Nguyen MH, Kapoor PS, Luus L, Sullivan A, Bortolato A, Svensson M, Hickey ER, Konze KD, Day T, Kim B, Negri A, Gerasyuto AI, Moy TI, Lu M, Ray AS, Wang L, Cui D, Lin FY, Lippa B, Rogers BN J Med Chem. 2024 Nov 14;67(21):18656-18681. doi: 10.1021/acs.jmedchem.4c01851. , Epub 2024 Oct 24. PMID:39446989 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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