Molecular basis of activation of the prototypic class B G protein-coupled secretin receptor
原型 B 类 G 蛋白偶联促胰液素受体激活的分子基础
基本信息
- 批准号:10468293
- 负责人:
- 金额:$ 37.23万
- 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 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityAgonistAntibodiesAnxietyBindingBiochemicalBiologicalBiological AssayCardiovascular DiseasesCardiovascular PhysiologyCholestasisComplementComplexCoupledCryoelectron MicroscopyCyclic AMPCysteineDataDependenceDevelopmentDiabetes MellitusDimerizationDistalDockingEpitopesEventExhibitsExtracellular DomainFamily memberFluorescence Resonance Energy TransferFunding MechanismsG-Protein-Coupled ReceptorsGTP-Binding ProteinsGlobal ChangeGoalsGrantHeterotrimeric GTP-Binding ProteinsImmunologicsInvestigationKnowledgeLengthLigand BindingLigandsMapsMental DepressionMetabolicMetabolic syndromeMethodologyMigraineModelingMolecularMolecular ConformationMutagenesisN-terminalNatureObesityOralOsteoporosisPathway interactionsPeptidesPharmaceutical PreparationsPhotoaffinity LabelsPlayPositioning AttributeProductionProteinsPruritusReceptor ActivationReceptor SignalingRefractoryResolutionRoleSecretinSeriesSignal PathwaySignal TransductionSiteSpecificityStructureSurfaceTechniquesTestingTherapeuticVariantWorkanalogantagonistdesigndisulfide bonddrug developmentexperiencegastrointestinalinsightnovelparticlepharmacophorereceptorreceptor functionreceptor structure functionsecretin receptorsmall moleculethree dimensional structuretool
项目摘要
PROJECT SUMMARY/ABSTRACT
Our OVERALL OBJECTIVE is to elucidate the molecular basis of activation of class B GPCRs, using the
prototypic secretin receptor (SecR) as a model. Insights will fill key gaps in knowledge and facilitate ultimate
development of drugs exhibiting various activity profiles. Class B GPCRs include established targets for
treatment of diabetes, obesity, osteoporosis, migraine, anxiety, and depression. However, therapeutics remain
suboptimal, and the receptor class has been refractory to development of small molecule, orally active drugs,
at least in part, due to lack of understanding of the structure and functional dynamics required for receptor
activation. We now have novel, unique insights into both of these, including high-resolution structures of
related, full-length, G protein-coupled holoreceptors, that highlight the importance of the interface between the
receptor N-terminal extracellular domain (ECD) and the transmembane domain core in ligand binding and
receptor activation. Component aims are directed toward understanding the conformational dynamics of this
interface for agonist binding and receptor activation, and using our breakthroughs in use of single particle cryo-
EM to provide a structural framework for this work. Aim 1, elucidates molecular events involved in secretin
peptide engagement with its receptor core, and key determinants for its activity, testing the hypothesis that
orientation (and interaction) of ECD and core domains plays a critical role in directing and positioning the
orthosteric agonist pharmacophore near its site of action. We will explore this locus using cysteine trapping to
compare spatial approximations for analogous inactive and active probes, applied to wild type receptor, as well
as dimerization-deficient receptor constructs. Rational structure-activity analysis for binding and a broad range
of biological activities of the agonist pharmacophore will also be performed, with results used to provide
insights into determinants of activation and effector specificity. Aim 2, investigates the relative orientations and
interactions between SecR ECD and core, exploring functional implications of this interrelationship, testing the
hypothesis that these domains can interact in various ways that affect states of quiescence and activation. This
will be approached by receptor mutagenesis to modify domain interactions, establishment of domain-domain
disulfide bonds by incorporating cysteines at the top of the receptor core and bottom of the ECD, as well as
using immunologic probes of predicted surfaces of the receptor amino terminus to determine access and to be
used in resonance transfer techniques. Aim 3, elucidates SecR inactive and active/holostructure using single
particle cryo-EM, testing the hypothesis that mapping of biochemical and functional data onto high resolution
3D structures, including agonist-receptor-heterotrimeric G protein and inactive antagonist-occupied receptor,
will help to elucidate the molecular basis for receptor signaling. Together, this work will provide fundamental
advances in understanding of class B GPCR structure and function, with insights highly useful in drug
development targeting these receptors.
项目总结/文摘
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Secretin Amino-Terminal Structure-Activity Relationships and Complementary Mutagenesis at the Site of Docking to the Secretin Receptor.
促胰液素氨基末端结构-活性关系和与促胰液素受体对接位点的互补诱变。
- DOI:10.1124/molpharm.122.000502
- 发表时间:2022
- 期刊:
- 影响因子:3.6
- 作者:Milburn,JulianaE;Harikumar,KaleeckalG;Piper,SarahJ;Raval,Sweta;Christopoulos,Arthur;Wootten,Denise;Sexton,PatrickM;Miller,LaurenceJ
- 通讯作者:Miller,LaurenceJ
Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors.
- DOI:10.3390/ijms23158069
- 发表时间:2022-07-22
- 期刊:
- 影响因子:5.6
- 作者:
- 通讯作者:
Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors.
- DOI:10.1146/annurev-pharmtox-010919-023301
- 发表时间:2020-01
- 期刊:
- 影响因子:12.5
- 作者:D. Wootten;L. Miller
- 通讯作者:D. Wootten;L. Miller
New Insights into the Structure and Function of Class B1 GPCRs.
- DOI:10.1210/endrev/bnac033
- 发表时间:2023-05-08
- 期刊:
- 影响因子:20.3
- 作者:
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
LAURENCE J MILLER其他文献
LAURENCE J MILLER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('LAURENCE J MILLER', 18)}}的其他基金
Impact of membrane composition on cholecystokinin receptor structure and function
膜成分对胆囊收缩素受体结构和功能的影响
- 批准号:
10541873 - 财政年份:2022
- 资助金额:
$ 37.23万 - 项目类别:
Impact of membrane composition on cholecystokinin receptor structure and function
膜成分对胆囊收缩素受体结构和功能的影响
- 批准号:
10364103 - 财政年份:2022
- 资助金额:
$ 37.23万 - 项目类别:
Molecular basis of activation of the prototypic class B G protein-coupled secretin receptor
原型 B 类 G 蛋白偶联促胰液素受体激活的分子基础
- 批准号:
10238892 - 财政年份:2019
- 资助金额:
$ 37.23万 - 项目类别:
Universal positive allosteric modulators of CCK1R without intrinsic agonist activity for the treatment of obesity
用于治疗肥胖症的无内在激动剂活性的 CCK1R 通用正变构调节剂
- 批准号:
9918929 - 财政年份:2018
- 资助金额:
$ 37.23万 - 项目类别:
Activation of the Secretin Receptor as a Strategy for the Treatment of Heart Failure
激活促胰液素受体作为治疗心力衰竭的策略
- 批准号:
9303747 - 财政年份:2017
- 资助金额:
$ 37.23万 - 项目类别:
Secretin Receptor Structure, Function, and Regulation
促胰液素受体的结构、功能和调节
- 批准号:
7905571 - 财政年份:2009
- 资助金额:
$ 37.23万 - 项目类别:
Secretin Receptor Structure, Function, and Regulation
促胰液素受体的结构、功能和调节
- 批准号:
7578221 - 财政年份:2005
- 资助金额:
$ 37.23万 - 项目类别:
Secretin Receptor Structure, Function, and Regulation
促胰液素受体的结构、功能和调节
- 批准号:
6874061 - 财政年份:2005
- 资助金额:
$ 37.23万 - 项目类别:
Secretin Receptor Structure, Function, and Regulation
促胰液素受体的结构、功能和调节
- 批准号:
7101768 - 财政年份:2005
- 资助金额:
$ 37.23万 - 项目类别:
Secretin Receptor Structure, Function, and Regulation
促胰液素受体的结构、功能和调节
- 批准号:
7208955 - 财政年份:2005
- 资助金额:
$ 37.23万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 37.23万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 37.23万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 37.23万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 37.23万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 37.23万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 37.23万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 37.23万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 37.23万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 37.23万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 37.23万 - 项目类别:
Grant-in-Aid for Early-Career Scientists