The aims of this proposal are to (1) improve comparative modeling so that atomic level accuracy models can be routinely generated starting from structures of homologous proteins, (2) transform the process of NMR structure determination by making possible the determination of atomic level accuracy models without side chain assignments, and (3) enable the determination of high resolution structures from 3-4.5 E resolution density maps. These methodological advances will be extended to enable structure determination of membrane proteins and large homo-oligomers based on datasets not sufficient to allow structure determination using conventional methods.

Public Health Relevance

The proposed work could transform the process of macromolecular structure determination, making it possible to determine accurate structures rapidly with less cost and effort, and to determine atomic level structures for proteins and complexes for which this is not currently possible. Such structures could provide insight into fundamental biological processes and the basis for disease causing mutations, and allow the structure based design of new therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM092802-03
Application #
8249839
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter C
Project Start
2010-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$292,077
Indirect Cost
$99,027
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Park, Hahnbeom; DiMaio, Frank; Baker, David (2016) CASP11 refinement experiments with ROSETTA. Proteins 84 Suppl 1:314-22
Safarian, Schara; Rajendran, Chitra; Müller, Hannelore et al. (2016) Structure of a bd oxidase indicates similar mechanisms for membrane-integrated oxygen reductases. Science 352:583-6
Wang, Ray Yu-Ruei; Kudryashev, Mikhail; Li, Xueming et al. (2015) De novo protein structure determination from near-atomic-resolution cryo-EM maps. Nat Methods 12:335-8
DiMaio, Frank; Song, Yifan; Li, Xueming et al. (2015) Atomic-accuracy models from 4.5-Ã… cryo-electron microscopy data with density-guided iterative local refinement. Nat Methods 12:361-5
Kudryashev, Mikhail; Wang, Ray Yu-Ruei; Brackmann, Maximilian et al. (2015) Structure of the type VI secretion system contractile sheath. Cell 160:952-62
Antala, Sagar; Ovchinnikov, Sergey; Kamisetty, Hetunandan et al. (2015) Computation and Functional Studies Provide a Model for the Structure of the Zinc Transporter hZIP4. J Biol Chem 290:17796-805
Ovchinnikov, Sergey; Kinch, Lisa; Park, Hahnbeom et al. (2015) Large-scale determination of previously unsolved protein structures using evolutionary information. Elife 4:e09248
Blok, Neil B; Tan, Dongyan; Wang, Ray Yu-Ruei et al. (2015) Unique double-ring structure of the peroxisomal Pex1/Pex6 ATPase complex revealed by cryo-electron microscopy. Proc Natl Acad Sci U S A 112:E4017-25
Park, Hahnbeom; DiMaio, Frank; Baker, David (2015) The origin of consistent protein structure refinement from structural averaging. Structure 23:1123-8
Ovchinnikov, Sergey; Kamisetty, Hetunandan; Baker, David (2014) Robust and accurate prediction of residue-residue interactions across protein interfaces using evolutionary information. Elife 3:e02030

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