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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：
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
项目类别：
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

项目摘要

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.

项目总结/文摘

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

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

嵌入大环中的短热稳定α-螺旋的设计。