7UKO
Integrin alpha IIB beta3 complex with sibrafiban (Mn)
Summary for 7UKO
| Entry DOI | 10.2210/pdb7uko/pdb |
| Related | 7L8P 7UDG 7UE0 7UFH 7UH8 7UJK 7UK9 |
| Descriptor | Integrin alpha-IIb heavy chain, GLYCEROL, MANGANESE (II) ION, ... (15 entities in total) |
| Functional Keywords | complex, inhibitor, blood clotting, cell adhesion, cell adhesion-inhibitor complex, cell adhesion/inhibitor |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 8 |
| Total formula weight | 302459.80 |
| Authors | Lin, F.-Y.,Zhu, J.,Zhu, J.,Springer, T.A. (deposition date: 2022-04-01, release date: 2022-08-17, Last modification date: 2024-10-16) |
| 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 Cited by 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: 36113427DOI: 10.1016/j.cell.2022.08.008 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.604 Å) |
Structure validation
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