Biophysical mechanisms of gating and modulation in voltage-gated ion channel superfamily
电压门控离子通道超家族的门控和调节的生物物理机制
基本信息
- 批准号:10609452
- 负责人:
- 金额:$ 98.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-03 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAlgorithmic AnalysisArchitectureArrhythmiaBindingBiological ModelsBiophysical ProcessBrainChemicalsCyclic NucleotidesDevelopmentDiseaseElementsEpilepsyExhibitsFluorometryFunctional disorderHeartHigh temperature of physical objectIon ChannelIon Channel GatingLengthLifeLigand BindingLigandsMeasuresMembraneModelingMolecularMolecular ProbesMusclePropertyProtein DynamicsProteinsRegulationSecond Messenger SystemsSignal TransductionSpectrum AnalysisStimulusStructureTemperatureTemperature SenseTestingThermodynamicsdriving forcedrug developmenthigh throughput analysisinsightmembermutantnew therapeutic targetnovel strategiesnovel therapeuticsreceptorreconstructionresponsesimulationsingle moleculesupercomputertoolvoltagevoltage clampwaveguide
项目摘要
Project Summary
Members of the voltage-gated ion channels (VGICs) are critical for electrical and chemical signaling throughout
the three kingdoms of life. Dysfunction of ion channels underlie a wide range of pathophysiology and they are
one of the primary targets for new drug development. Although they share a common membrane architecture,
the channels in this superfamily exhibit surprising diversity of function. Most open in response to a membrane
depolarization but some open on hyperpolarization. Many of them are also polymodal- their activity is regulated
by second messengers such as cyclic nucleotide or a physical stimulus such as temperature. The main objective
of this proposal is to probe the molecular driving forces in order to understand the fundamental mechanisms of
voltage-gating and its modulation by temperature and ligand. Current mechanistic approach tends to be structure
focused to the extent that protein dynamics is either ignored or treated as secondary. Although the structures of
many highly temperature-sensitive ion channels are now available, our understanding of the mechanism of tem-
perature-sensitivity remains limited, in large part, due to our inability to directly probe the molecular forces. To
address this issue, we are using a multi-pronged approach that combines new and existing tools to systematically
characterize the molecular interactions that determine polarity of voltage-gating, exquisite temperature-sensitiv-
ity and unusual allostery in VGICs. We are using the HCN channel as a model system to study gating polarity
and ligand activation. Using zero model waveguides and newly developed high-throughput analysis algorithms
we were able to probe the cooperativity of ligand binding in a model system. We are now poised to extend these
studies to full-length channels and receptors. With regards to mechanisms of gating polarity, we have made a
surprising discovery that a bipartite switch regulates gating polarity in HCN channels. Microsecond scale simu-
lations in Anton supercomputer suggest a gating model which we will be tested further. We will carry out structural
studies and combine it with voltage clamp fluorometry in order to annotate these structures. Next, we will also
use ancestral protein reconstruction approach, to identify the deep allosteric networks that regulate gating po-
larity in these channels. Our studies on temperature-dependent gating is based on two model systems: a) Tem-
perature-sensitive Shaker mutant and, b) archaeal MthK channel. In order to determine the essential elements
that are responsible for “sensing” temperature, we have to measure the thermodynamic properties such as heat
capacity. We propose to develop a new approach involving single molecule force spectroscopy to extract these
energetic parameters. Overall, our “molecular forces” focused approach has the potential to provide unparalleled
insights into the mechanisms of voltage gating and its regulation by temperature in VGICs.
项目总结
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
Baron Chanda其他文献
Baron Chanda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('Baron Chanda', 18)}}的其他基金
TriMED: Measuring, Modeling and Manipulating Excitability and Disease
TriMED:测量、建模和操纵兴奋性和疾病
- 批准号:
10627404 - 财政年份:2023
- 资助金额:
$ 98.55万 - 项目类别:
Biophysical mechanisms of gating and modulation in voltage-gated ion channel superfamily
电压门控离子通道超家族的门控和调节的生物物理机制
- 批准号:
10266191 - 财政年份:2020
- 资助金额:
$ 98.55万 - 项目类别:
Biophysical mechanisms of gating and modulation in voltage-gated ion channel superfamily
电压门控离子通道超家族的门控和调节的生物物理机制
- 批准号:
10225212 - 财政年份:2020
- 资助金额:
$ 98.55万 - 项目类别:
Biophysical mechanisms of gating and modulation in voltage-gated ion channel superfamily
电压门控离子通道超家族的门控和调节的生物物理机制
- 批准号:
10400913 - 财政年份:2020
- 资助金额:
$ 98.55万 - 项目类别:
Synthetic design of an all-optical electrophysiology system
全光学电生理系统的综合设计
- 批准号:
10225934 - 财政年份:2019
- 资助金额:
$ 98.55万 - 项目类别:
Mechanisms of voltage- and ligand-activation in HCN channels
HCN 通道中电压和配体激活的机制
- 批准号:
10225052 - 财政年份:2017
- 资助金额:
$ 98.55万 - 项目类别:
Thermodynamics and energetics of voltage-gated ion channels
电压门控离子通道的热力学和能量学
- 批准号:
8690188 - 财政年份:2012
- 资助金额:
$ 98.55万 - 项目类别:
Thermodynamics and Energetics of voltage-gated ion channels
电压门控离子通道的热力学和能量学
- 批准号:
10226481 - 财政年份:2012
- 资助金额:
$ 98.55万 - 项目类别:
Thermodynamics and energetics of voltage-gated ion channels
电压门控离子通道的热力学和能量学
- 批准号:
8544516 - 财政年份:2012
- 资助金额:
$ 98.55万 - 项目类别:
Thermodynamics and energetics of voltage-gated ion channels
电压门控离子通道的热力学和能量学
- 批准号:
8422219 - 财政年份:2012
- 资助金额:
$ 98.55万 - 项目类别:
相似海外基金
AI-based prediction of the belepharoptosis etiologies by means of machine learning algorithmic analysis of length-tensile force chart of levator muscle
通过提上睑肌长度-拉力图的机器学习算法分析,基于人工智能的上睑下垂病因预测
- 批准号:
22K09863 - 财政年份:2022
- 资助金额:
$ 98.55万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Algorithmic analysis of symmetric-key cryptographic primitives
对称密钥密码原语的算法分析
- 批准号:
262074-2008 - 财政年份:2013
- 资助金额:
$ 98.55万 - 项目类别:
Discovery Grants Program - Individual
Algorithmic analysis of symmetric-key cryptographic primitives
对称密钥密码原语的算法分析
- 批准号:
262074-2008 - 财政年份:2012
- 资助金额:
$ 98.55万 - 项目类别:
Discovery Grants Program - Individual
Algorithmic analysis of symmetric-key cryptographic primitives
对称密钥密码原语的算法分析
- 批准号:
262074-2008 - 财政年份:2011
- 资助金额:
$ 98.55万 - 项目类别:
Discovery Grants Program - Individual
Unified Approach for Nanotechnology CAD/Computation by Algorithmic Analysis of Periodic Crystal Structures
通过周期性晶体结构的算法分析实现纳米技术 CAD/计算的统一方法
- 批准号:
22650002 - 财政年份:2010
- 资助金额:
$ 98.55万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Algorithmic analysis of symmetric-key cryptographic primitives
对称密钥密码原语的算法分析
- 批准号:
262074-2008 - 财政年份:2010
- 资助金额:
$ 98.55万 - 项目类别:
Discovery Grants Program - Individual
Algorithmic analysis of symmetric-key cryptographic primitives
对称密钥密码原语的算法分析
- 批准号:
262074-2008 - 财政年份:2009
- 资助金额:
$ 98.55万 - 项目类别:
Discovery Grants Program - Individual
Algorithmic analysis of symmetric-key cryptographic primitives
对称密钥密码原语的算法分析
- 批准号:
262074-2008 - 财政年份:2008
- 资助金额:
$ 98.55万 - 项目类别:
Discovery Grants Program - Individual
Mathematical & Algorithmic Analysis of Natural and Artificial DNA Sequences
数学
- 批准号:
0218568 - 财政年份:2002
- 资助金额:
$ 98.55万 - 项目类别:
Standard Grant
Algorithmic Analysis and Congestion Control of Connection-Oriented Services in Large Scale Communication Networks.
大规模通信网络中面向连接的服务的算法分析和拥塞控制。
- 批准号:
9404947 - 财政年份:1994
- 资助金额:
$ 98.55万 - 项目类别:
Standard Grant