Structural and Functional Studies of Potassium Channels by Solid State NMR
通过固态核磁共振研究钾通道的结构和功能
基本信息
- 批准号:10021668
- 负责人:
- 金额:$ 35.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-30 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAmino AcidsArrhythmiaBehaviorBindingCardiacCell Signaling ProcessChemicalsCommunicable DiseasesCoupledCouplingDataDiseaseDistalDrug TargetingEventEvolutionExhibitsFreezingFrequenciesGrantHealthHeartHumanHydration statusInvestigationIon ChannelIonsLaboratoriesLengthLifeLigand BindingLigandsLong QT SyndromeMalignant NeoplasmsMeasurementMediatingMedicalMembraneMembrane PotentialsMethodsModelingMolecularMolecular ConformationMutagenesisMutationNatureNervous System PhysiologyNervous system structureNeuronsParticipantPharmaceutical PreparationsPhysiologic pulsePhysiologicalPlayPotassium ChannelProcessPropertyProtein RegionRegulationRegulatory ElementRestRoleSignal TransductionSiteStructureStudy modelsSyndromeSystemTestingThermodynamicsTimeWorkbasedesignexperienceexperimental studyextracellularhuman pathogeninsightmutantnanosecondpotassium ionreceptorresponsesensorsolid state nuclear magnetic resonancetool
项目摘要
Abstract
Potassium channels control numerous signaling processes for humans and pathogens. Essentially all
characterized K+ channels inactivate spontaneously after opening, due to a transmembrane allosteric
process that acts to control mean open time. Inactivation modulates function for many important channels
and drug targets: for example, neurons use K+ channel inactivation to modulate their firing frequency, and
inactivation in the channels of the human heart has strong effects on heart timing. Our recent work provided
evidence that the molecular basis of C type inactivation in KcsA is transmembrane allosteric coupling, where
opening of the intracellular activation gate causes the extracellular selectivity filter to lose its affinity for K+. We
showed that this transmembrane allosteric coupling is strong in the wild type channel in bilayers and absent in
several inactivation-less mutants. In the upcoming period we plan to delineate the mechanism for this
transmembrane allosteric control of channel activity. In our first aim, we will systematically identify residues that
participate in the mechanism, i.e. residues that “sense” and “couple” both binding phenomena and mediate the
allosteric response. We will implement an NMR chemical shift based strategy to identify likely candidates. To
confirm the key role of candidate sites, we will manipulate the strength of the coupling through mutation at
these sites. The functional hallmark of allostery, modulation of ligands’ affinities through binding of another,
distal ligand, will be probed by NMR to quantitatively assess the impact of mutation on coupling. In our second
aim, we will determine the structure of the Activated state and contrast key interactions involving the allosteric
participants in the Activated state vs the Deactivated (Resting) and Inactivated states, to test hypotheses about
the molecular basis for allostery. The Activated state is the only state that transmits ions, and is the key
metastable intermediate of allosteric response. The structure of the wild type activated channel in bilayers has
been elusive. In contrast to other kinds of studies, our SSNMR studies are done on hydrated, wild type
channels in bilayers; the pH and ion concentrations are freely varied. In the previous grant period, we identified
conditions for preparing the Activated state. In our third aim we will characterize dynamic exchange processes
in the Activated state in order to obtain insights into spontaneous Inactivation. We will use recently developed
rotating frame solid state NMR pulse sequences that allow measurement at numerous sites, minimizing
unwanted coherent evolution of the spins. We will contrast the conformational dynamics of the Activated state
in hydrated bilayers to other states of the system (Deactivated, Inactivated). By comparing the exchange
timescales and amplitudes to those expected from MD-based models of activation coupled inactivation we will
test a variety of mechanisms for allosteric inactivation of ion channels.
摘要
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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ANN E MCDERMOTT其他文献
ANN E MCDERMOTT的其他文献
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{{ truncateString('ANN E MCDERMOTT', 18)}}的其他基金
HIGH FIELD/HIGH FREQUENCY ESR FOR STUDYING DNP IN BIOMEMBRANES
用于研究生物膜中 DNP 的高场/高频 ESR
- 批准号:
8364114 - 财政年份:2011
- 资助金额:
$ 35.98万 - 项目类别:
DYNAMIC NUCLEAR POLARIZATION SOLID STATE NMR SPECTROMETER FOR BIOMOLECULAR STUDIE
用于生物分子研究的动态核偏振固态核磁共振波谱仪
- 批准号:
7839443 - 财政年份:2010
- 资助金额:
$ 35.98万 - 项目类别:
Structural and Functional Studies of Potassium Channels by Solid State NMR
通过固态核磁共振研究钾通道的结构和功能
- 批准号:
10460945 - 财政年份:2009
- 资助金额:
$ 35.98万 - 项目类别:
Structural and Functional Studies of Channels and Pumps by Solid State NMR
通过固态核磁共振研究通道和泵的结构和功能
- 批准号:
8325732 - 财政年份:2009
- 资助金额:
$ 35.98万 - 项目类别:
Structural and Functional Studies of Potassium Channels by Solid State NMR
通过固态核磁共振研究钾通道的结构和功能
- 批准号:
8760232 - 财政年份:2009
- 资助金额:
$ 35.98万 - 项目类别:
Structural and Functional Studies of Channels and Pumps by Solid State NMR
通过固态核磁共振研究通道和泵的结构和功能
- 批准号:
7941916 - 财政年份:2009
- 资助金额:
$ 35.98万 - 项目类别:
Structural and Functional Studies of Channels and Pumps by Solid State NMR
通过固态核磁共振研究通道和泵的结构和功能
- 批准号:
8142738 - 财政年份:2009
- 资助金额:
$ 35.98万 - 项目类别:
Structural and Functional Studies of Potassium Channels by Solid State NMR
通过固态核磁共振研究钾通道的结构和功能
- 批准号:
9117619 - 财政年份:2009
- 资助金额:
$ 35.98万 - 项目类别:
Structural and Functional Studies of Potassium Channels by Solid State NMR
通过固态核磁共振研究钾通道的结构和功能
- 批准号:
10224775 - 财政年份:2009
- 资助金额:
$ 35.98万 - 项目类别:
Structural and Functional Studies of Potassium Channels by Solid State NMR
通过固态核磁共振研究钾通道的结构和功能
- 批准号:
10659941 - 财政年份:2009
- 资助金额:
$ 35.98万 - 项目类别:
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