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Platelet alphaIIbbeta3 activation and its therapeutic targeting

血小板αIIbbeta3激活及其治疗靶向

基本信息

批准号：
10004711
负责人：
M. AMIN ARNAOUT
金额：
$ 53.35万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004711
关键词：
3-Dimensional Adhesions Affinity Agonist Agreement American Binding Binding Sites Biological Availability Blood Platelets Cardiology Cell membrane Cessation of life Collaborations Complex Cryoelectron Microscopy Crystallization Crystallography Cytoplasmic Tail Data Detergents Development Drug Design Drug Targeting Early treatment European Event Excision Face Guidelines Hemorrhage Hemostatic function Heterogeneity Hospitals Immune Impairment Integral Membrane Protein Integrins Leg Length Libraries Life Ligand Binding Ligands Link Measures Membrane Membrane Potentials Methodology Modeling Molecular Conformation Monitor Myocardial Infarction Nature Negative Staining Pathologic Patients Peptide Synthesis Peptides Pharmaceutical Preparations Phase Platelet aggregation Pre-hospital setting Preparation Primates Prior Therapy Proteins Publishing Receptor Activation Recombinants Regulation Reporting Resolution Risk Role Signal Transduction Societies Solid Structure Structure-Activity Relationship Surface Plasmon Resonance Technology Testing Therapeutic Thrombocytopenia Thrombosis Transmembrane Domain Water X-Ray Crystallography adverse outcome attack victim base clinical efficacy coronary thrombus design eptifibatide high risk improved improved outcome inhibitor/antagonist insight interdisciplinary approach mimetics mouse model novel percutaneous coronary intervention prevent receptor response small molecule structured data therapeutic target three dimensional structure tomography two-dimensional

项目摘要

Abstract Platelet αIIbβ3 is required for normal hemostasis, but is also a validated drug target because of its essential role in pathologic thrombosis. αIIbβ3 is normally kept in an inactive bent conformation on circulating platelets, but rapidly switches to an active (ligand-binding) conformation in response to inside-out signaling. The ligand- occupied receptor then transmits outside-in signals via the αβ transmembrane (TM) and cytoplasmic domains that initiate platelet adhesion, a response inadvertently produced by current orthosteric inhibitory drugs, which has limited their clinical efficacy. The structural basis of bidirectional integrin signaling remains to be clarified. One model suggests that the ligand-binding site directly faces the plasma membrane in the bent conformation, with integrin genuextension required for access to ligand. However, the integrin ectodomain/TM tilt has not been defined experimentally. Further, regulated αβ TM domain association in integrins is driven by the ectodomain, which may explain some of the differences found in the reported NMR structures of the isolated αIIbβ3 TM domains. In preliminary studies, we produce a low-resolution cryo-EM structure of full-length αIIbβ3 in an unexpected orientation relative to the membrane, the result of its complex in cis with a tetraspanner, providing the first experimental definition of an integrin ectodomain/TM tilt, and novel insights into the structural basis of αIIbβ3 activation. We also develop a water soluble, stable and high affinity orthosteric inhibitor of αIIbβ3 that is not a partial agonist, and use it in a structure-guided approach to generate like compounds. We propose to expand on these preliminary data in three specific aims, utilizing multidisciplinary approaches that include electron cryomicroscopy, tomography, protein crystallography, structure-based drug design, new peptide synthesis technology and novel murine models of thrombosis.

摘要