6naj

Integrin AlphaVBeta3 ectodomain bound to Hr10 variant of the 10th domain of Fibronectin.

spinqualitylabelsall models 6naj, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6naj is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.1Å Ligands: BMA, HRG, 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 A prevailing dogma is that inhibition of vascular thrombosis by antagonizing platelet integrin alphaIIbbeta3 cannot be achieved without compromising hemostasis, thus causing serious bleeding and increased morbidity and mortality. It is speculated that these adverse outcomes result from drug-induced activating conformational changes in alphaIIbbeta3 but direct proof is lacking. Here, we report the structure-guided design of peptide Hr10 and a modified form of the partial agonist drug tirofiban that act as "pure" antagonists of alphaIIbbeta3, i.e., they no longer induce the conformational changes in alphaIIbbeta3. Both agents inhibit human platelet aggregation but preserve clot retraction. Hr10 and modified tirofiban are as effective as partial agonist drugs in inhibiting vascular thrombosis in humanized mice, but neither causes serious bleeding, establishing a causal link between partial agonism and impaired hemostasis. Pure orthosteric inhibitors of alphaIIbbeta3 may thus provide safer alternatives for human therapy, and valuable tools to probe structure-activity relationships in integrins. Structure-guided design of pure orthosteric inhibitors of alphaIIbbeta3 that prevent thrombosis but preserve hemostasis.,Adair BD, Alonso JL, van Agthoven J, Hayes V, Ahn HS, Yu IS, Lin SW, Xiong JP, Poncz M, Arnaout MA Nat Commun. 2020 Jan 21;11(1):398. doi: 10.1038/s41467-019-13928-2. PMID:31964886 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Fibronectin 3D structures Integrin 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA