Deciphering the relationship between structure, dynamics and function in helical bundle proteins
解读螺旋束蛋白的结构、动力学和功能之间的关系
基本信息
- 批准号:10172923
- 负责人:
- 金额:$ 71.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmantadineAmantadine resistanceAntibodiesBacteriaCollaborationsCompanionsComplexComputing MethodologiesCoupledCrystallizationCuesDrug DesignEnvironmentEpidermal Growth Factor ReceptorGeometryGrantInfluenzaInfluenza A virusInorganic Phosphate TransporterIntegral Membrane ProteinIntegrinsIonsLengthLigandsLipidsMeasurementMembraneMembrane ProteinsMethodsModelingMolecular ConformationMovementNational Institute of General Medical SciencesNutrientPeptidesPharmaceutical PreparationsProcessPropertyProtein EngineeringProtein RegionProteinsProtonsReagentResolutionSeriesSignal TransductionStructureTechniquesTemperatureTestingTransition ElementsTransmembrane DomainWaterWorkbasecofactordesignmodel designmutantoxidationprotein structure functionprotein-histidine kinasesingle moleculesmall molecule inhibitorx-ray free-electron laser
项目摘要
Project Summary/Abstract
This proposal combines my two NIGMS grants. Our work on the M2 proton channel from influenza A
virus (GM56423) currently focuses on the mechanism of proton movement through the channel. M2 is also the
target of the amantadine class of influenza drugs, and most isolates of influenza A virus are now amantadine-
resistant. Crystallographic structures of M2 in various functional states will be solved at very high resolution
using the X-ray free electron laser to enable structure determination at room temperature. Parallel,
collaborative studies use single-molecule measurement and 2DIR to probe dynamics. Very high-resolution
structures of a series of small molecule inhibitors in complex with amantadine-resistant mutants of M2 are
being determined, to enable our collaborators to conduct structure-based drug design.
De novo protein design (GM54616) provides a means to test and refine our understanding of protein
structure and function. We address questions of sequence-specific recognition in membranes. A variety of
methods exist for the design or selection of antibodies and other reagents that recognize the water-soluble
regions of proteins. However, companion methods for targeting Transmembrane (TM) regions are not
generally available. Therefore, we are developing methods for the computational design of peptides that target
TM helices in a sequence-specific manner, focusing on EGF receptors (collaboration with Natalia Jura) and
integrins (collaboration with A. Orr). To elucidate the mechanisms by which proton-coupled transporters
function, we have designed model proteins that use proton gradients to drive transport of transition metal ions
up a gradient. We are increasing the efficiency of these minimal models and also expanding our methods to
allow design of phosphate transporters and lipid flippases. We propose to continue work on the design of
model diiron proteins to determine how a protein tunes the properties of these cofactors to affect diverse O2-
dependent processes such as substrate oxidation and radical formation. We are designing water and
membrane-soluble versions of the protein; by varying the identity and geometry of ligands and the water-
accessibility of the center to determine how these parameters they define reactivity.
We are studying the mechanisms by which bacterial histidine kinases transmit conformational
information through multi-domain TM proteins. HKs are widely used by bacteria to sense and respond to
diverse environmental cues such as nutrients or noxious substances. Crystal structures of various truncated
domains of HKs have been solved. However, there are no high-resolution structures for HK membrane-
spanning domains or full-length HKs, and their signaling mechanism is a matter of debate. By integrating
structural information from diverse experimental techniques and functional measurements of HKs we seek to
elucidate the mechanism of signaling in HKs.
59
项目摘要/摘要
这项提案结合了我的两笔NIGMS赠款。我们在甲型流感M2质子通道上的工作
病毒(GM56423)目前主要关注质子通过该通道的运动机制。M2也是
金刚烷胺类流感药物的靶标,现在甲型流感病毒的大多数分离株都是金刚烷胺-
抵抗力强。M2在各种功能状态下的晶体结构将在很高的分辨率下得到解决
使用X射线自由电子激光在室温下进行结构测定。平行的,
合作研究使用单分子测量和2DIR来探测动力学。非常高的分辨率
一系列小分子抑制剂与金刚烷胺耐药突变株M2的复合体结构
正在下定决心,使我们的合作者能够进行基于结构的药物设计。
从头开始蛋白质设计(GM54616)提供了一种测试和改进我们对蛋白质的理解的方法
结构和功能。我们解决了膜中序列特异性识别的问题。各种各样的
存在用于设计或选择识别水溶性的抗体和其他试剂的方法
蛋白质的区域。然而,用于靶向跨膜(TM)区域的配套方法不是
一般都能买到。因此,我们正在开发针对以下目标的多肽的计算设计方法
TM螺旋以序列特定的方式,专注于EGF受体(与Natalia Jura合作)和
整合素(与A.Orr合作)。阐明质子偶联转运体的作用机制
功能,我们设计了使用质子梯度来驱动过渡金属离子运输的模型蛋白质。
向上倾斜。我们正在提高这些最小模型的效率,并将我们的方法扩展到
允许设计磷酸盐转运体和脂类转运酶。我们建议继续进行设计工作,
模拟双铁蛋白以确定蛋白质如何调节这些辅因子的性质以影响不同的O2-
依赖的过程,如底物氧化和自由基的形成。我们正在设计水和
膜可溶的蛋白质版本;通过改变配体和水的特性和几何形状-
中心的可达性,以确定这些参数如何定义反应性。
我们正在研究细菌组氨酸激酶传递构象的机制。
通过多结构域TM蛋白提供信息。HKS被细菌广泛使用来感知和响应
不同的环境线索,如营养素或有毒物质。各种截断的晶体结构
已经解决了HKS的域问题。然而,目前还没有用于香港膜的高分辨率结构-
跨域或全长HKS,以及它们的信令机制是有争议的。通过集成
我们从不同的实验技术和功能测量中寻求HKS的结构信息
阐明HKS信号转导机制。
59
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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WILLIAM DEGRADO其他文献
WILLIAM DEGRADO的其他文献
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{{ truncateString('WILLIAM DEGRADO', 18)}}的其他基金
Targeting Viroporins and Coronavirus M Protein
靶向病毒孔蛋白和冠状病毒 M 蛋白
- 批准号:
10512629 - 财政年份:2022
- 资助金额:
$ 71.19万 - 项目类别:
Deciphering the relationship between structure, dynamics and function in helical bundle proteins
解读螺旋束蛋白的结构、动力学和功能之间的关系
- 批准号:
10703499 - 财政年份:2017
- 资助金额:
$ 71.19万 - 项目类别:
Deciphering the relationship between structure, dynamics and function in helical bundle proteins
解读螺旋束蛋白的结构、动力学和功能之间的关系
- 批准号:
10406742 - 财政年份:2017
- 资助金额:
$ 71.19万 - 项目类别:
Deciphering the relationship between structure, dynamics and function in helical bundle proteins
解读螺旋束蛋白的结构、动力学和功能之间的关系
- 批准号:
9977222 - 财政年份:2017
- 资助金额:
$ 71.19万 - 项目类别:
Treatment of pulmonary fibrosis with inhibitors of integrin alphavbeta1.
用整合素αvβ1抑制剂治疗肺纤维化。
- 批准号:
8931040 - 财政年份:2014
- 资助金额:
$ 71.19万 - 项目类别:
Treatment of pulmonary fibrosis with inhibitors of integrin alphavbeta1.
用整合素αvβ1抑制剂治疗肺纤维化。
- 批准号:
9144901 - 财政年份:2014
- 资助金额:
$ 71.19万 - 项目类别:
Treatment of pulmonary fibrosis with inhibitors of integrin alphavbeta1.
用整合素αvβ1抑制剂治疗肺纤维化。
- 批准号:
9310063 - 财政年份:2014
- 资助金额:
$ 71.19万 - 项目类别:
Treatment of pulmonary fibrosis with inhibitors of integrin alphavbeta1.
用整合素αvβ1抑制剂治疗肺纤维化。
- 批准号:
8748498 - 财政年份:2014
- 资助金额:
$ 71.19万 - 项目类别:
Vaccines that Replicate the Neutralization-Competent Structure of the gp41 MPER
复制 gp41 MPER 中和能力结构的疫苗
- 批准号:
8263672 - 财政年份:2012
- 资助金额:
$ 71.19万 - 项目类别:
Vaccines that Replicate the Neutralization-Competent Structure of the gp41 MPER
复制 gp41 MPER 中和能力结构的疫苗
- 批准号:
8625268 - 财政年份:2012
- 资助金额:
$ 71.19万 - 项目类别:
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