9AXL

Structure of the semi-extended AlphaIIbBeta3 in complex with R21D10 Fab

9AXL の概要

• エントリーDOI: 10.2210/pdb9axl/pdb
• EMDBエントリー: 43969
• 分子名称: Integrin alpha-IIb, Integrin beta-3, R21D10 Fab heavy chain, ... (7 entities in total)
• 機能のキーワード: monoclonal antibody, integrin receptor, allosteric inhibitor, platelets, blood clotting, blood clotting-immune system complex, blood clotting/immune system
• 由来する生物種: Mus musculus; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 248777.18

構造登録者

Wang, J.L.,Walz, T.,Coller, B.,Wang, L.,Li, J.H. (登録日: 2024-03-06, 公開日: 2024-11-13, 最終更新日: 2024-11-27)

主引用文献

Wang, L.,Wang, J.,Li, J.,Walz, T.,Coller, B.S.
An alpha IIb beta 3 monoclonal antibody traps a semiextended conformation and allosterically inhibits large ligand binding.
Blood Adv, 8:4398-4409, 2024

PubMed Abstract: Monoclonal antibodies (mAbs) have provided valuable information regarding the structure and function of platelet αIIbβ3. Protein disulfide isomerase (PDI) has been implicated in αIIbβ3 activation and binds to thrombin-activated αIIbβ3. Using human platelets as the immunogen, we identified a new mAb (R21D10) that inhibits the binding of PDI to platelets activated with thrombin receptor-activating peptide (T6). R21D10 also partially inhibited T6-induced fibrinogen and PAC-1 binding to platelets, as well as T6- and adenosine 5'-diphosphate-induced platelet aggregation. Mutual competition experiments showed that R21D10 does not inhibit the binding of mAbs 10E5 (anti-αIIb cap domain) or 7E3 (anti-β3 β-I domain), and immunoblot studies indicated that R21D10 binds to β3. The dissociation of αIIbβ3 by EDTA had a minimal effect on R21D10 binding. Cryogenic electron microscopy of the αIIbβ3-R21D10 Fab complex revealed that R21D10 binds to the β3 integrin-epidermal growth factor 1 (I-EGF1) domain and traps an intermediate conformation of αIIbβ3 with semiextended leg domains. The binding of R21D10 produces a major structural change in the β3 I-EGF2 domain associated with a new interaction between the β3 I-EGF2 and αIIb thigh domains, which may prevent the swing-out motion of the β3 hybrid domain required for high-affinity ligand binding and protect αIIbβ3 from EDTA-induced dissociation. R21D10 partially reversed the ligand binding priming effect of eptifibatide, suggesting that it could convert the swung-out conformation into a semiextended conformation. We concluded that R21D10 inhibits ligand binding to αIIbβ3 via a unique allosteric mechanism, which may or may not be related to its inhibition of PDI binding.

PubMed: 38968144
DOI: 10.1182/bloodadvances.2024013177

実験手法

ELECTRON MICROSCOPY (3.3 Å)