Cited by 359Protein Kinase Regulation and GTPase SignalingReceptor Mechanisms and SignalingProtein Structure and Dynamics

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Ras Conformational Ensembles, Allostery, and Signaling

Lu, Shaoyong, Jang, Hyunbum, Muratcioglu, Serena, Gursoy, Attila, Keskin, Ozlem, Nussinov, Ruth, Zhang, Jian·2016·Chemical Reviews

DOI 10.1021/acs.chemrev.5b00542

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Abstract

Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the conformational ensembles and the allosteric regulation of Ras proteins and their interpretation from our conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modifications, and different membrane compositions. A better understanding of Ras biology can contribute to therapeutic strategies.

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Authors: Lu, S., Jang, H., Muratcioglu, S., Gursoy, A., Keskin, O., Nussinov, R., & Zhang, J.
Affiliations: Shanghai Jiao Tong University (CN)
Frederick National Laboratory for Cancer Research (US)
Tel Aviv University (IL)
Corresponding author: Nussinov, Ruth
Zhang, Jian
ORCID: Lu, Shaoyong
Jang, Hyunbum
Nussinov, Ruth
Zhang, Jian
Venue: Chemical Reviews
Publisher: American Chemical Society (ACS)
Published: 2016-01-27
Volume: 116
Issue: 11
Pages: 6607-6665
ISSN: 0009-2665 (ISSN-L)
1520-6890
DOI: 10.1021/acs.chemrev.5b00542
OpenAlex: W2260312731
Cited by: 355
References: 457
Citations by year: 2026: 23 · 2025: 26 · 2024: 30 · 2023: 40 · 2022: 47 · 2021: 35 · 2020: 39 · 2019: 38 · 2018: 29 · 2017: 30 · 2016: 18
FWCI: 3.46
Type: journal article
Language: en
Open access: closed
Locations: Chemical Reviews (publishedVersion)
PubMed (publishedVersion)
Funders: Program for New Century Excellent Talents in University (NCET-12-0355)
National Cancer Institute (HHSN261200800001E)
Ministry of Science and Technology of the People's Republic of China (2015CB910403)
Science and Technology Commission of Shanghai Municipality (13QA1402300)
National Natural Science Foundation of China (81302698, 81322046, 81473137)
Shanghai Municipal Health and Family Planning Commission (20154Y0058)
Collaborative Innovation Center of Systems Biomedicine
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords: Ras proteins, small GTPases, conformational ensembles, allosteric regulation, Ras signaling, guanine nucleotide exchange factor, GTPase-activating protein, post-translational modification, membrane composition, RAS mutations
MeSH terms: Allosteric Regulation, Guanosine Triphosphate, Protein Binding, Signal Transduction, Protein Structure, Tertiary, ras Proteins, Nuclear Magnetic Resonance, Biomolecular, Catalytic Domain

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Ras Conformational Ensembles, Allostery, and Signaling

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