6NAJ
Integrin AlphaVBeta3 ectodomain bound to Hr10 variant of the 10th domain of Fibronectin.
Summary for 6NAJ
| Entry DOI | 10.2210/pdb6naj/pdb |
| Related | 3IJE 4MMZ |
| Descriptor | Integrin alpha-V, Integrin beta-3, Fibronectin, HR10 variant, ... (9 entities in total) |
| Functional Keywords | hybrid domain, psi, egf repeats, beta tail, calf, thigh, beta propeller, rgd motif, fibronectin, vitronectin, cell adhesion |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 197249.80 |
| Authors | van Agthoven, J.,Arnaout, M.A. (deposition date: 2018-12-05, release date: 2019-12-11, Last modification date: 2023-11-15) |
| Primary citation | Adair, B.D.,Alonso, J.L.,van Agthoven, J.,Hayes, V.,Ahn, H.S.,Yu, I.S.,Lin, S.W.,Xiong, J.P.,Poncz, M.,Arnaout, M.A. Structure-guided design of pure orthosteric inhibitors of alpha IIb beta 3 that prevent thrombosis but preserve hemostasis. Nat Commun, 11:398-398, 2020 Cited by PubMed Abstract: A prevailing dogma is that inhibition of vascular thrombosis by antagonizing platelet integrin αIIbβ3 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 αIIbβ3 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 αIIbβ3, i.e., they no longer induce the conformational changes in αIIbβ3. 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 αIIbβ3 may thus provide safer alternatives for human therapy, and valuable tools to probe structure-activity relationships in integrins. PubMed: 31964886DOI: 10.1038/s41467-019-13928-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.1 Å) |
Structure validation
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