8tcg | pdb_00008tcg

Integrin alpha-v beta-6 in complex with minibinder B6_BP_dslf

spinqualitylabelsall models 8tcg, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8tcg is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.4Å Ligands: BMA, CA, MAN, MN, 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 The RGD (Arg-Gly-Asp)-binding integrins alphavbeta6 and alphavbeta8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous alphavbeta6 and alphavbeta8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective alphavbeta6 and alphavbeta8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the alphavbeta6 and the alphavbeta8 integrins. In a lung fibrosis mouse model, the alphavbeta6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity. De novo design of highly selective miniprotein inhibitors of integrins alphavbeta6 and alphavbeta8.,Roy A, Shi L, Chang A, Dong X, Fernandez A, Kraft JC, Li J, Le VQ, Winegar RV, Cherf GM, Slocum D, Poulson PD, Casper GE, Vallecillo-Zuniga ML, Valdoz JC, Miranda MC, Bai H, Kipnis Y, Olshefsky A, Priya T, Carter L, Ravichandran R, Chow CM, Johnson MR, Cheng S, Smith M, Overed-Sayer C, Finch DK, Lowe D, Bera AK, Matute-Bello G, Birkland TP, DiMaio F, Raghu G, Cochran JR, Stewart LJ, Campbell MG, Van Ry PM, Springer T, Baker D Nat Commun. 2023 Sep 13;14(1):5660. doi: 10.1038/s41467-023-41272-z. PMID:37704610 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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