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
• 负责人: WILLIAM DEGRADO
• 金额: $ 71.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703499
• 关键词: Alkali Metals; Amantadine; Amantadine resistance; Amino Acids; Binding Proteins; Computing Methodologies; Coronavirus; Crystallography; Drug Design; Future; Hydration status; Influenza; Influenza A virus; Ion Channel; Ions; Membrane; Membrane Proteins; Metalloporphyrins; Movement; Nutrient; Pathway interactions; Pharmaceutical Preparations; Protein Engineering; Proteins; Protons; Stretching; Structure; Testing; Therapeutic; Viral; Virus; Water; Work; design; in vivo; protein function; protein structure; resistant strain; small molecule

Project Summary/Abstract This proposal combines work on viral ion channels and de novo protein design. Our work on the M2 proton channel from influenza A virus focuses on the mechanism of inhibition and 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. Crystallography, computation and 2DIR will be used to interrogate the mechanism and aid in design of drugs that inhibit M2 in amantadine-resistant strains of the virus. In parallel, we will expand our studies to examine the mechanism of conduction and inhibition of the E-proteins from coronaviruses, which have structures and functions largely similar to M2. De novo protein design provides a means to test and refine our understanding of protein structure and function. We are developing computational methods to design proteins that bind small molecules such as drugs and metalloporphyrins. We are also designing membrane proteins to elucidate the principles by which they fold and function. To probe the mechanisms of highly selective proton conduction proteins, we are designing proton-selective channels that test a hypothesis that networks of water molecules (water wires) can form dynamically and transiently through apolar stretches of the proton conduction pathway in proteins. The water wires would allow conduction of protons but not large hydrated alkali metal ions such as K+ or Na+. We also are engaged in design of proteins that bind to and transport nutrients such as amino acids across membranes, and devising screens to test them in vivo.

项目概要/摘要 该提案结合了病毒离子通道和从头蛋白质设计的工作。我们在 M2 上的工作 甲型流感病毒的质子通道侧重于通过抑制和质子运动的机制 频道。 M2 也是金刚烷胺类流感药物和大多数甲型流感病毒分离株的靶标 病毒现已对金刚烷胺产生抗药性。晶体学、计算和 2DIR 将用于询问 机制并有助于设计抑制金刚烷胺抗性病毒株中的 M2 的药物。并联， 我们将扩大我们的研究范围，以检查 E 蛋白的传导和抑制机制 冠状病毒，其结构和功能与 M2 非常相似。 从头蛋白质设计提供了一种测试和完善我们对蛋白质结构的理解的方法 功能。我们正在开发计算方法来设计结合小分子的蛋白质，例如 药物和金属卟啉。我们还设计了膜蛋白来阐明其原理 它们折叠并发挥作用。为了探究高选择性质子传导蛋白的机制，我们 设计质子选择性通道来测试水分子网络（水线）可以 通过蛋白质中质子传导途径的非极性延伸动态且短暂地形成。这 水线可以传导质子，但不能传导大的水合碱金属离子，例如 K+ 或 Na+。我们 还从事蛋白质的设计，这些蛋白质可以结合并运输营养物质，例如氨基酸 膜，并设计屏幕来对其进行体内测试。

项目成果

Behaviour and interactions of proteins and peptides with and within membranes; from simple models to cellular membranes: general discussion.

蛋白质和肽在膜上和膜内的行为和相互作用；

• DOI: 10.1039/d1fd90067f
• 发表时间: 2021
• 期刊: Faraday discussions
• 影响因子: 3.4
• 作者: Aguilar,Mibel;AlNahas,Kareem;Barrera,Francisco;Bassereau,Patricia;Bastos,Margarida;Beales,Paul;Bechinger,Burkhard;Bonev,Boyan;Brand,Izabella;Chattopadhyay,Amitabha;DeGrado,William;Fuchs,Patrick;GarciaSaez,AnaJ;Hoogenboom,Bart
• 通讯作者: Hoogenboom,Bart

Rimantadine Binds to and Inhibits the Influenza A M2 Proton Channel without Enantiomeric Specificity.

• DOI: 10.1021/acs.biochem.1c00437
• 发表时间: 2021-08-03
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Thomaston JL;Samways ML;Konstantinidi A;Ma C;Hu Y;Bruce Macdonald HE;Wang J;Essex JW;DeGrado WF;Kolocouris A
• 通讯作者: Kolocouris A

De Novo Design of Tetranuclear Transition Metal Clusters Stabilized by Hydrogen-Bonded Networks in Helical Bundles.

螺旋束中氢键网络稳定的四核过渡金属簇的从头设计。

• DOI: 10.1021/jacs.7b08261
• 发表时间: 2018
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Zhang,Shao-Qing;Chino,Marco;Liu,Lijun;Tang,Youzhi;Hu,Xiaozhen;DeGrado,WilliamF;Lombardi,Angela
• 通讯作者: Lombardi,Angela

Design of a Short Thermally Stable α-Helix Embedded in a Macrocycle.

• DOI: 10.1002/cbic.201800026
• 发表时间: 2018-05-04
• 期刊: Chembiochem : a European journal of chemical biology
• 作者: Wu H;Acharyya A;Wu Y;Liu L;Jo H;Gai F;DeGrado WF
• 通讯作者: DeGrado WF

Entry from the Lipid Bilayer: A Possible Pathway for Inhibition of a Peptide G Protein-Coupled Receptor by a Lipophilic Small Molecule.

• DOI: 10.1021/acs.biochem.8b00577
• 发表时间: 2018-10-02
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Bokoch MP;Jo H;Valcourt JR;Srinivasan Y;Pan AC;Capponi S;Grabe M;Dror RO;Shaw DE;DeGrado WF;Coughlin SR
• 通讯作者: Coughlin SR