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:10251142
- 负责人:
- 金额:$ 53.35万
- 依托单位:
- 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:
- 关键词:3-DimensionalAdhesionsAffinityAgonistAgreementAmericanBindingBinding SitesBiological AvailabilityBlood PlateletsCardiologyCell membraneCessation of lifeCollaborationsComplexCryoelectron MicroscopyCrystallizationCrystallographyCytoplasmic TailDataDetergentsDevelopmentDrug DesignDrug TargetingEarly treatmentEuropeanEventExcisionFaceGuidelinesHemorrhageHemostatic functionHeterogeneityHospitalsImmuneImpairmentIntegral Membrane ProteinIntegrinsLegLengthLibrariesLifeLigand BindingLigandsLinkMeasuresMembraneMembrane PotentialsMethodologyModelingMolecular ConformationMonitorMyocardial InfarctionNatureNegative StainingPathologicPatientsPeptide SynthesisPeptidesPharmaceutical PreparationsPhasePlatelet aggregationPre-hospital settingPreparationPrimatesPrior TherapyProteinsPublishingReceptor ActivationRecombinantsRegulationReportingResolutionRiskRoleSignal TransductionSocietiesSolidStructureStructure-Activity RelationshipSurface Plasmon ResonanceTechnologyTestingTherapeuticThrombocytopeniaThrombosisTransmembrane DomainWaterX-Ray Crystallographyadverse outcomeattack victimbaseclinical efficacycoronary thrombusdesigneptifibatidehigh riskimprovedimproved outcomeinhibitor/antagonistinsightinterdisciplinary approachmimeticsmouse modelnovelpercutaneous coronary interventionpreventreceptorresponsesmall moleculetherapeutic targetthree dimensional structuretomographytwo-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
血小板αIIbβ3是正常止血所必需的,但也是一个经过验证的药物靶点,因为它具有重要的
病理性血栓形成的作用。αIIbβ3通常在循环血小板上保持无活性的弯曲构象,
但响应于由内向外的信号传导而迅速转变为活性(配体结合)构象。配体-
被占据的受体然后通过αβ跨膜(TM)和胞质结构域传递由外向内的信号
其引发血小板粘附,这是由目前的正构抑制药物无意中产生的反应,
限制了其临床疗效。双向整合素信号传导的结构基础仍有待澄清。
一种模型认为,配体结合位点在弯曲构象中直接面对质膜,
其中整合素β延伸是接近配体所必需的。然而,整联蛋白胞外域/TM倾斜并没有
被实验定义。此外,整联蛋白中调节的αβ TM结构域缔合是由αβ TM结构域驱动的。
胞外域,这可以解释在报道的分离的化合物的NMR结构中发现的一些差异。
αIIbβ3 TM结构域。在初步研究中,我们制作了全长αIIbβ3的低分辨率冷冻电镜结构,
在相对于膜的意想不到的方向上,其与四跨膜剂顺式复合的结果,
提供了整合素胞外域/TM倾斜的第一个实验定义,以及对整合素胞外域/TM倾斜的新见解。
αIIbβ3激活的结构基础。我们还开发了一种水溶性的、稳定的、高亲和力的正构
非部分激动剂αIIbβ3抑制剂,并将其用于结构指导的方法以产生类似
化合物.我们建议在三个具体目标中扩展这些初步数据,利用多学科
包括电子低温显微镜、断层扫描、蛋白质晶体学、基于结构的药物
设计,新的肽合成技术和新的小鼠血栓形成模型。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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M. AMIN ARNAOUT其他文献
M. AMIN ARNAOUT的其他文献
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{{ truncateString('M. AMIN ARNAOUT', 18)}}的其他基金
Targeting innate immunity for induction of robust renal allograft tolerance
针对先天免疫诱导强大的肾同种异体移植耐受
- 批准号:
10622050 - 财政年份:2023
- 资助金额:
$ 53.35万 - 项目类别:
Effects of combining anti-CD40 and anti-CD11b mAb107 on survival of pig kidney xenografts in cynomolgus monkeys
抗CD40和抗CD11b mAb107联合使用对食蟹猴猪肾异种移植物存活的影响
- 批准号:
10425736 - 财政年份:2022
- 资助金额:
$ 53.35万 - 项目类别:
Effects of combining anti-CD40 and anti-CD11b mAb107 on survival of pig kidney xenografts in cynomolgus monkeys
抗CD40和抗CD11b mAb107联合使用对食蟹猴猪肾异种移植物存活的影响
- 批准号:
10618872 - 财政年份:2022
- 资助金额:
$ 53.35万 - 项目类别:
Platelet alphaIIbbeta3 activation and its therapeutic targeting
血小板αIIbbeta3激活及其治疗靶向
- 批准号:
10469477 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
Platelet alphaIIbbeta3 activation and its therapeutic targeting
血小板αIIbbeta3激活及其治疗靶向
- 批准号:
10004711 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
Role of integrin CD11b in delayed graft function and allorejection
整合素 CD11b 在移植物功能延迟和同种异体排斥中的作用
- 批准号:
9809349 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
Structure and Function of Integrins in the Kidney
肾脏中整合素的结构和功能
- 批准号:
10375579 - 财政年份:2010
- 资助金额:
$ 53.35万 - 项目类别:
Structure and function of integrins in the kidney
肾脏整合素的结构和功能
- 批准号:
9354435 - 财政年份:2010
- 资助金额:
$ 53.35万 - 项目类别:
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