Rational Design from Cryo-EM Structures of High-Affinity Ryanodine Receptor Ligands Based on Natural Peptides
Rational Design from Cryo-EM Structures of High-Affinity Ryanodine Receptor Ligands Based on Natural Peptides
批准号:
10729564
负责人:
Hector H Valdivia
金额:
$66.4万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-10 至 2027-06-30
关键词:
Adrenergic AgentsAffectAffinityAgonistAmino AcidsAnimal ModelAnimalsAreaArrhythmiaArrhythmogenic Right Ventricular DysplasiaAtrial FibrillationBindingBiological AssayBiologyCardiacCardiac MyocytesCardiomyopathiesCatecholaminergic Polymorphic Ventricular TachycardiaCellsChildComplexCouplingCryoelectron MicroscopyDNA Sequence AlterationDevelopmentDiastoleDiseaseFamilyFunctional disorderGenetic TranscriptionGoalsHeartHeart DiseasesHeart failureHyperactivityHypertrophic CardiomyopathyIndividualIonsKnock-inLabelLigandsLinkMarketingMediatingMembraneModelingMolecularMusMuscle CellsMuscle FibersMutationOryctolagus cuniculusPathologicPenetrationPeptidesPerfusionPermeabilityPharmaceutical PreparationsPharmacotherapyPhasePlayProcessPropertyRationalizationReceptor GeneRoleRyR2Ryanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumScorpionsSeriesSiteSpecificityStructureSudden DeathSyndromeTechniquesTestingTherapeuticTransmembrane DomainVenomsVentricularVentricular TachycardiaVestibuleanalogdesigneffective therapygain of function mutationinsightmembermutantnanomolarnovelpharmacologicpreventprogramsrational designstemtranscription factoryoung adult
中文摘要
摘要
Ryanodine受体(RyRs)是肌浆网(SR)的钙释放通道,在肌浆网(SR)中发挥重要作用。
心肌和骨骼肌细胞兴奋收缩偶联中的重要作用。心脏RyR基因的突变
(RYR2)与致心律失常的儿茶酚胺能多形性室性心动过速(CPVT)相关
以肾上腺素介导的室性心动过速和猝死为特征的综合征。
CPVT显然是一种致心律失常的疾病,源于RyR2引起的细胞内钙离子处理不当
功能障碍。因此,从CPVT综合征中获得的见解有助于我们机械地理解其他
在心肌病中,RyR2连接的钙离子错误处理起着关键作用。RyR2功能障碍导致
通过诱导肌浆网钙离子“泄漏”和/或自发性钙离子释放(Scr)对心脏产生有害影响
触发心律失常活动的临界质量的钙离子。因此,控制RyR2的过度活动可以缓解SR的钙离子浓度
“漏”和避免SCR是主要心肌病治疗方案的主要目标。一群球状的
被称为Calcins的多肽以高亲和力和特异性靶向RyRs。Imperacalcin(IPCA),该组织的创始成员
钙蛋白家族通过其宽阔的前庭进入并以精致的精度结合到一个部位来与RyRs接触
在通道的胞质“帽”深处,与跨膜区相邻,充当“推动”的楔子。
横向上,排列在通道孔内的跨膜螺旋,使其打开并产生长寿命的
次导电态。在CPVT动物模型中,IPCA穿透心肌细胞外膜
并诱导肌浆网钙离子部分耗竭,从而阻止SCR,并有效地缓解肾上腺素介导的
钙超载,触发钙依赖型心律失常。因此,IPCA自然地作为RyRs的激动剂,
SCR是心律失常的主要触发因素的心肌病的抗心律失常作用,并通过合理设计
IPCA类似物能够关闭它与RYR创造的自然“凹槽”,它具有切实的潜力成为
第一个高亲和力的RyR阻滞剂,可能会防止SR的钙“泄漏”。钙蛋白-RyR络合物的低温电子显微镜结构
和一系列功能分析,Aim 1将确定钙蛋白的结构域,使它们能够与
RyR具有精致的亲和力和特异性,并产生能够阻断RyR离子传导的钙素类似物。
Aim 2将使用交感神经刺激时容易产生SCR的CPVT小鼠品系和一种新的兔CPVT
提供结构性SR钙泄漏和病理性心脏重塑的模型,以确定天然和
突变的钙蛋白能够预防RyR功能障碍引发的心律失常。我们的多学科项目,包括
定义明确的交付成果和里程碑,并由两名结构(Van Petegem)和功能PIS专家领导
(Valdia)RyRs的生物学,将产生一种治疗钙依赖型心律失常的新范例,该地区
现有的药物治疗严重不足。
英文摘要
SUMMARY
Ryanodine receptors (RyRs), are the Ca2+ release channels of sarcoplasmic reticulum (SR) that play an
essential role in excitaton-contraction coupling of cardiac and skeletal muscle cells. Mutations in the cardiac RyR gene
(RYR2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmogenic
syndrome characterized by the development of adrenergically-mediated ventricular tachycardia and sudden death.
CPVT is clearly an arrhythmogenic disorder stemming from intracellular Ca2+ mishandling caused by RyR2
dysfunction. As such, insights gained from CPVT syndromes benefit our mechanistic understanding of other
cardiomyopathies where RyR2-linked Ca2+ mishandling plays a pivotal role. RyR2 dysfunction brings about
deleterious effects in the heart by inducing SR Ca2+ “leak” and/or spontaneous Ca2+ release (SCR), a sudden, diastolic
Ca2+ bolous of critical mass that triggers arrhythmic activity. Thus, reigning in RyR2 hyperactivity to mitigate SR Ca2+
“leak” and avoid SCR is a primary goal of therapeutic regimes for major cardiomyopathies. A group of globular
peptides termed calcins target RyRs with high affinity and specificity. Imperacalcin (IpCa), the founding member of
the calcin family, engages RyRs by entering through their wide vestibule and binding with exquisite precision to a site
deep in the cytosolic “cap” of the channel, adjacent to the transmembrane region, acting as a wedge that “pushes”
laterally the transmembrane helices that line the channel pore, causing it to open and giving rise to a long-lived
subconductance state. In animal models of CPVT, IpCa penetrates the external membrane of ventricular myocytes
and induces a partial depletion of SR Ca2+, thus preventing SCR and in effect relieving the adrenergically-mediated
Ca2+ overload that triggers Ca2+-dependent arrhythmias. Thus, IpCa behaves naturally as an agonist of RyRs, with
anti-arrhytmic effect in cardiomyopathies where SCR is the primary trigger of arrhythmias, and by rational design of
IpCa analogs capable of closing the natural “grooves” it creates with RyRs, it has the tangible potential to become
the first high-affinity RyR blocker that may prevent SR Ca2+ “leak”. Using cryo-EM structures of calcin-RyR complexes
and a series of functional assays, aim 1 will determine the structural domains of calcins that allow them to bind to
RyRs with exquisite affinity and specificity, and to generate calcin analogs capable of blocking RyR ion conduction.
Aim 2 will use CPVT mouse lines that readily present SCR during sympathetic stimulation and a novel rabbit CPVT
model that presents constitutive SR Ca2+ leak and pathological cardiac remodeling to determine whether native and
mutant calcins are capable of preventing RyR dysfunction-triggered arrhythmias. Our multi-disciplnary program, with
well-defined deliverables and milestones and led by two PIs experts in structural (Van Petegem) and functional
(Valdivia) biology of RyRs, will produce a novel paradigm for the treatment of Ca2+-dependent arrhythmias, an area
severely underserved by existent pharmacotherapy.
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会议论文
Natural Agonists of Ryanodine Receptors: Structure-function Relationship and Antiarrhythmic Properties
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批准号:9905552
-
项目类别:
-
资助金额:$46.32万
-
财政年份:2017
-
负责人:Hector H Valdivia
-
依托单位:
2017 Muscle: Excitation-Contraction Coupling Gordon Research Conference and Gordon Research Seminar
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批准号:9331041
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项目类别:
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资助金额:$2.3万
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财政年份:2017
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负责人:Hector H Valdivia
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依托单位:
Natural Agonists of Ryanodine Receptors: Structure-function Relationship and Antiarrhythmic Properties
-
批准号:9650244
-
项目类别:
-
资助金额:$46.18万
-
财政年份:2017
-
负责人:Hector H Valdivia
-
依托单位:
Cytosolic Calcium Sweeper in Cardiac Myocytes
-
批准号:9266807
-
项目类别:
-
资助金额:$31.73万
-
财政年份:2014
-
负责人:Hector H Valdivia
-
依托单位:
Cytosolic Calcium Sweeper in Cardiac Myocytes
-
批准号:9646518
-
项目类别:
-
资助金额:$7.02万
-
财政年份:2014
-
负责人:Hector H Valdivia
-
依托单位:
Calcins as Membrane-permeable Ligands of Ryanodine Receptors
-
批准号:8301588
-
项目类别:
-
资助金额:$38.48万
-
财政年份:2011
-
负责人:Hector H Valdivia
-
依托单位:
Calcins as Membrane-permeable Ligands of Ryanodine Receptors
-
批准号:8464216
-
项目类别:
-
资助金额:$34.57万
-
财政年份:2011
-
负责人:Hector H Valdivia
-
依托单位:
Calcins as Membrane-permeable Ligands of Ryanodine Receptors
-
批准号:8098484
-
项目类别:
-
资助金额:$35.57万
-
财政年份:2011
-
负责人:Hector H Valdivia
-
依托单位:
Calcins as Membrane-permeable Ligands of Ryanodine Receptors
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批准号:8663945
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项目类别:
-
资助金额:$34.93万
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财政年份:2011
-
负责人:Hector H Valdivia
-
依托单位:
Modulation of Cardiac E-C Coupling by Sorcin
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批准号:6777329
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项目类别:
-
资助金额:$36.15万
-
财政年份:2004
-
负责人:Hector H Valdivia
-
依托单位:
Modulation of Cardiac E-C Coupling by Sorcin
-
批准号:7023828
-
项目类别:
-
资助金额:$35.28万
-
财政年份:2004
-
负责人:Hector H Valdivia
-
依托单位:
Modulation of Cardiac E-C Coupling by Sorcin
-
批准号:6861092
-
项目类别:
-
资助金额:$36.14万
-
财政年份:2004
-
负责人:Hector H Valdivia
-
依托单位:
Modulation of Cardiac E-C Coupling by Sorcin
-
批准号:7210701
-
项目类别:
-
资助金额:$34.25万
-
财政年份:2004
-
负责人:Hector H Valdivia
-
依托单位:
Modulation of Cardiac E-C Coupling by Sorcin
-
批准号:7385060
-
项目类别:
-
资助金额:$34.25万
-
财政年份:2004
-
负责人:Hector H Valdivia
-
依托单位:
RYANODINE RECEPTORS AND ACCESSORY PROTEINS
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批准号:6600932
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项目类别:
-
资助金额:$19.96万
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财政年份:2002
-
负责人:Hector H Valdivia
-
依托单位:
RYANODINE RECEPTORS AND ACCESSORY PROTEINS
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批准号:6643678
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项目类别:
-
资助金额:$19.96万
-
财政年份:2002
-
负责人:Hector H Valdivia
-
依托单位:
RYANODINE RECEPTORS AND ACCESSORY PROTEINS
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批准号:6479454
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项目类别:
-
资助金额:$19.96万
-
财政年份:2001
-
负责人:Hector H Valdivia
-
依托单位:
MODULATORY MECHANISMS OF RYANODINE RECEPTOR ADAPTATION
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批准号:6389530
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项目类别:
-
资助金额:$25.2万
-
财政年份:1996
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负责人:Hector H Valdivia
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依托单位:
MODULATORY MECHANISMS OF RYANODINE RECEPTOR ADAPTATION
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批准号:2668760
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项目类别:
-
资助金额:$14.33万
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财政年份:1996
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负责人:Hector H Valdivia
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依托单位:
beta-adrenergic modulation of cardiac ryanodine receptor
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批准号:7112388
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项目类别:
-
资助金额:$31.72万
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财政年份:1996
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负责人:Hector H Valdivia
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依托单位:
海外基金