Structural Dynamics in Rhodopsin Activation and Attenuation
视紫红质激活和衰减的结构动力学
基本信息
- 批准号:10611423
- 负责人:
- 金额:$ 38.5万
- 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:2019-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:11 cis RetinalAddressAffectAffinityAgonistApoptosisArrestinsAttenuatedBindingCattleColor VisionsComplementComplexComputing MethodologiesConeData AnalysesDiseaseDrug TargetingEnabling FactorsEncapsulatedEquilibriumEventExhibitsFamilyFoundationsG-Protein-Coupled ReceptorsGRK1 geneGTP-Binding ProteinsGoalsHealthHumanHuman GenomeKineticsLigand BindingLigandsLightLipidsMolecularMolecular ChaperonesMolecular ConformationMutationNight BlindnessNonexudative age-related macular degenerationOpsinPharmaceutical PreparationsPharmacologic SubstancePharmacological TreatmentPhosphorylationPhotobleachingPhotoreceptorsPigmentsPlayProcessPropertyProteinsReceptor SignalingRefractoryResearchResearch DesignRetinaRetinal DegenerationRetinal DiseasesRetinal PigmentsRetinitis PigmentosaRhodopsinRoleRouteSequence HomologyStructureTechniquesTestingTimeTransducinVariantVertebrate PhotoreceptorsVisionVisual Signal Transduction PathwayWorkadductattenuationautosomebiophysical analysischromophoredesigndimerexperimental studyinsightnovelpharmacologicphotoactivationreceptorsmall moleculetooluptake
项目摘要
Project Summary
A long-term goal of our research is to understand the molecular mechanisms through which G-protein coupled
receptors (GPCRs) are activated and attenuated. GPCRs are the largest family in the human genome, and the
target of most pharmaceutical drugs. One exception has been rhodopsin – although the first GPCR
discovered, it has so far been refractory to direct pharmacological treatments.
Here the Kliger and Farrens lab join forces to define the dynamic events and mechanisms involved in the
photo-activation of human rhodopsin and cone photopsins, determine how rhodopsin interacts with its ligand,
retinal, determine how its function changes with mutations responsible for retinal diseases and determine how
these interactions enable, and are modulated by, interactions with its affiliate protein arrestin. Although the
structures of retinal, rhodopsin, and arrestin are now known, the dynamic processes that enable them to
interact with each other are not. Thus, the types of studies we propose here are required.
Specific Aim 1 will determine the photoactivation kinetics of human red and green cone pigments, determine
how the activation of human rhodopsin is short-circuited by mutations associated with ADRP, and test how
these kinetics are effected by small molecule chaperones used to treat and stabilize misfolded opsins. Specific
Aim 2 will determine what role novel receptor conformations play in the process of retinal uptake and release,
test if a previously unidentified receptor conformation enables binding of 11-cis retinal (11CR), and expand on
our discovery that opsin can transiently linger in an active-like state after releasing all-trans retinal (ATR).
Finally, Specific Aim 3 will determine if arrestin binding enables ATR to bind photobleached rhodopsin in
equilibrium, and define what effect arrestin binding to rhodopsin dimers has on this phenomenon.
Understanding what regulates the process of rhodopsin photoactivation, and retinal uptake and release, and
how arrestin regulates these actions is critically important from a health perspective. The retina must
accommodate huge variations in these events as it adapts to widely different light conditions, yet aberrations in
this process over time are thought to result in the formation of oxidative retinal adducts that promote diseases
like atrophic age-related macular degeneration (AMD). Thus, it appears that arrestin must walk a fine line – on
the one hand controlling the amount of free retinal released under varying light conditions, and on the other
releasing retinal and itself from the receptor at the appropriate time to avoid forming stable rhodopsin-arrestin
complexes that can contribute to apoptosis and some forms of retinitis pigmentosa.
The work here complements our recent discovery that ATR can exchange in equilibrium with some rhodopsin
photoproducts, and recent discoveries by others of non-retinal ligands that bind and stabilize misfolded opsins.
These findings dramatically increase the possibility that drugs can be developed to either compete with or
enhance retinal binding, thus opening the door for treating this key photoreceptor with pharmacological agents.
项目摘要
我们研究的一个长期目标是了解G蛋白偶联的分子机制
受体(GPCR)被激活和减弱。GPCR是人类基因组中最大的家族,
大多数药物的目标。一个例外是视紫红质-尽管第一个GPCR
发现,它迄今为止一直难以直接药物治疗。
在这里,Kliger和Farrens实验室联合起来定义了
人视紫红质和视锥细胞视紫红质的光活化,确定视紫红质如何与其配体相互作用,
视网膜,确定其功能如何随着视网膜疾病的突变而变化,并确定如何
这些相互作用使得能够与其附属蛋白抑制蛋白相互作用,并且通过与其附属蛋白抑制蛋白相互作用来调节。虽然
视网膜,视紫红质和抑制蛋白的结构现在是已知的,动态过程使它们能够
相互之间没有互动。因此,我们在这里提出的研究类型是必要的。
具体目标1将确定人红色和绿色锥状色素的光活化动力学,确定
人类视紫红质的激活是如何通过与ADRP相关的突变短路的,并测试如何
这些动力学受用于处理和稳定错误折叠视蛋白的小分子伴侣的影响。具体
目的2将确定新的受体构象在视网膜摄取和释放过程中起什么作用,
测试先前未鉴定的受体构象是否能够结合11-顺式视黄醛(11 CR),
我们发现视蛋白在释放全反式视黄醇(ATR)后可以暂时停留在活性样状态。
最后,特异性目标3将确定抑制蛋白结合是否使ATR能够结合光漂白的视紫红质。
平衡,并定义抑制蛋白与视紫红质二聚体的结合对这种现象有何影响。
了解什么调节视紫红质光活化过程,视网膜吸收和释放,
从健康的角度来看,arrestin如何调节这些行为至关重要。视网膜必须
适应这些事件中的巨大变化,因为它适应了广泛不同的光线条件,
随着时间的推移,这一过程被认为会导致氧化视网膜加合物的形成,
比如萎缩性年龄相关性黄斑变性(AMD)。因此,似乎arrestin必须走一条细线,
一方面控制在变化的光照条件下释放的游离视网膜的量,另一方面
在适当的时间从受体释放视网膜及其本身,以避免形成稳定的视紫红质抑制蛋白
复合物,可以有助于细胞凋亡和某些形式的视网膜色素变性。
这里的工作补充了我们最近的发现,ATR可以交换平衡与一些视紫红质
光产物,以及其他人最近发现的结合和稳定错误折叠视蛋白的非视网膜配体。
这些发现极大地增加了药物开发的可能性,
增强视网膜结合,从而打开了用药理学试剂治疗这一关键感光体的大门。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Styrene-Maleic Acid Copolymer Effects on the Function of the GPCR Rhodopsin in Lipid Nanoparticles.
- DOI:10.1016/j.bpj.2021.09.012
- 发表时间:2021-09
- 期刊:
- 影响因子:3.4
- 作者:I. Szundi;Stephanie G. Pitch;E. Chen;D. Farrens;D. Kliger
- 通讯作者:I. Szundi;Stephanie G. Pitch;E. Chen;D. Farrens;D. Kliger
{{
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 }}
David L Farrens其他文献
David L Farrens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('David L Farrens', 18)}}的其他基金
Structural Dynamics in Rhodopsin Activation and Attenuation
视紫红质激活和减弱的结构动力学
- 批准号:
9920141 - 财政年份:2019
- 资助金额:
$ 38.5万 - 项目类别:
Structural Dynamics in Rhodopsin Activation and Attenuation
视紫红质激活和衰减的结构动力学
- 批准号:
10399456 - 财政年份:2019
- 资助金额:
$ 38.5万 - 项目类别:
Structural Dynamics of Retinal Binding and Release
视网膜结合和释放的结构动力学
- 批准号:
8403607 - 财政年份:2006
- 资助金额:
$ 38.5万 - 项目类别:
Structural Dynamics of Retinal Binding and Release
视网膜结合和释放的结构动力学
- 批准号:
8197249 - 财政年份:2006
- 资助金额:
$ 38.5万 - 项目类别:
Structural Dynamics of Retinal Binding and Release
视网膜结合和释放的结构动力学
- 批准号:
8599774 - 财政年份:2006
- 资助金额:
$ 38.5万 - 项目类别:
Structural Dynamics of Retinal Binding and Release
视网膜结合和释放的结构动力学
- 批准号:
7094863 - 财政年份:2006
- 资助金额:
$ 38.5万 - 项目类别:
Structural Dynamics of Retinal Binding and Release
视网膜结合和释放的结构动力学
- 批准号:
7627968 - 财政年份:2006
- 资助金额:
$ 38.5万 - 项目类别:
Structural Dynamics of Retinal Binding and Release
视网膜结合和释放的结构动力学
- 批准号:
7435259 - 财政年份:2006
- 资助金额:
$ 38.5万 - 项目类别:
Structural Dynamics of Retinal Binding and Release
视网膜结合和释放的结构动力学
- 批准号:
7236576 - 财政年份:2006
- 资助金额:
$ 38.5万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Research Grant














{{item.name}}会员




