Normal Mode Analysis of KRas4B Reveals Partner Specific Dynamics
| Autor: | Ruth Nussinov, Hyunbum Jang, Ozlem Keskin, Meryem Eren, Attila Gursoy, Nurcan Tuncbag |
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| Přispěvatelé: | Tunçbağ, Nurcan (ORCID 0000-0002-0389-9459 & YÖK ID 245513), Gürsoy, Attila (ORCID 0000-0002-2297-2113 & YÖK ID 8745), Keskin Özkaya, Zehra Özlem (ORCID 0000-0002-4202-4049 & YÖK ID 26605), Eren, Meryem, Jang, Hyunbum, Nussinov, Ruth, School of Medicine, College of Engineering, Graduate School of Sciences and Engineering, Department of Molecular Biology and Genetics, Department of Chemical and Biological Engineering, Department of Computer Engineering |
| Rok vydání: | 2021 |
| Předmět: |
Anisotropic Network Model
Structural basis Catalytic site Hotspots Ras Proteins GTP Activation Mutations Motions Fluctuations Interfaces Monomers Protein structure Chemical structure Conformation Mutant Allosteric regulation Molecular Conformation Son of Sevenless GTPase Molecular Dynamics Simulation Article symbols.namesake Materials Chemistry Humans Physical and Theoretical Chemistry Binding site Binding Sites biology Chemistry Surfaces Coatings and Films ras Proteins symbols SOS1 Biophysics biology.protein Gaussian network model Allosteric Site Protein Binding |
| Zdroj: | J Phys Chem B Journal of Physical Chemistry B |
| ISSN: | 1520-5207 1520-6106 |
| Popis: | Ras GTPase interacts with its regulators and downstream effectors for its critical function in cellular signaling. Targeting the disrupted mechanisms in Ras-related human cancers requires understanding the distinct dynamics of these protein-protein interactions. We performed normal mode analysis (NMA) of KRas4B in wild-type or mutant monomeric and neurofibromin-1 (NF1), Son of Sevenless 1 (SOS1) or Raf-1 bound dimeric conformational states to reveal partner-specific dynamics of the protein. Gaussian network model (GNM) analysis showed that the known KRas4B lobes further partition into subdomains upon binding to its partners. Furthermore, KRas4B interactions with different partners suppress the flexibility in not only their binding sites but also distant residues in the allosteric lobe in a partner-specific way. The conformational changes can be driven by intrinsic residue fluctuations of the open state KRas4B-GDP, as we illustrated with anisotropic network model (ANM) analysis. The allosteric paths connecting the nucleotide binding residues to the allosteric site at alpha 3-L7 portray differences in the inactive and active states. These findings help in understanding the partner-specific KRas4B dynamics, which could be utilized for therapeutic targeting. National Cancer Institute; National Institutes of Health; Intramural Research Program of the NIH; Center for Cancer Research |
| Databáze: | OpenAIRE |
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