7THO

Integrin alpha IIB beta3 complex with Eptifibatide

Summary for 7THO

• Entry DOI: 10.2210/pdb7tho/pdb
• Related: 7TCT 7TD8
• Related PRD ID: PRD_002490
• Descriptor: Integrin alpha-IIb, SULFATE ION, MAGNESIUM ION, ... (13 entities in total)
• Functional Keywords: complex, inhibitor, blood clotting, blood clotting-inhibitor complex, blood clotting/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 300924.51

Authors

Zhu, J.,Lin, F.-Y.,Zhu, J.,Springer, T.A. (deposition date: 2022-01-11, release date: 2022-08-17, Last modification date: 2024-10-02)

Primary citation

Lin, F.Y.,Li, J.,Xie, Y.,Zhu, J.,Huong Nguyen, T.T.,Zhang, Y.,Zhu, J.,Springer, T.A.
A general chemical principle for creating closure-stabilizing integrin inhibitors.
Cell, 185:3533-3550.e27, 2022

PubMed Abstract: Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbβ3 and α4β1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbβ3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4β1.

PubMed: 36113427
DOI: 10.1016/j.cell.2022.08.008

Experimental method

X-RAY DIFFRACTION (2.75 Å)