A major current focus of modern structural biology is the determination of the structures of macromolecular assemblies and machines. Such systems are often not amenable to high-resolution x-ray crystallographic techniques. This proposal aims to develop powerful new methods which integrate NMR data, information from homologous structures, cryo electron microscopy data, low resolution x-ray crystallographic data, evolutionary covariance data, and other sources of information to generate models with atomic level accuracy for macromolecular assemblies and machines. With collaborators, the new methodology will be used to solve cutting-edge structural biology problems which cannot be solved by currently available methods. The new methodology will be incorporated into the freely available Rosetta software suite for use throughout the scientific community.

Public Health Relevance

Proteins are the workhorses of living things. The structures of proteins are critical to carrying out their functions. This research will contribute to determining the structures of protein assemblies critical to life and human disease.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Preusch, Peter
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University of Washington
Schools of Medicine
United States
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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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