6NAJ

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

6NAJ の概要

• エントリーDOI: 10.2210/pdb6naj/pdb
• 関連するPDBエントリー: 3IJE 4MMZ
• 分子名称: Integrin alpha-V, Integrin beta-3, Fibronectin, HR10 variant, ... (9 entities in total)
• 機能のキーワード: hybrid domain, psi, egf repeats, beta tail, calf, thigh, beta propeller, rgd motif, fibronectin, vitronectin, cell adhesion
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 197249.80

構造登録者

van Agthoven, J.,Arnaout, M.A. (登録日: 2018-12-05, 公開日: 2019-12-11, 最終更新日: 2023-11-15)

主引用文献

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

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: 31964886
DOI: 10.1038/s41467-019-13928-2

実験手法

X-RAY DIFFRACTION (3.1 Å)