title: Ras Conformational Ensembles, Allostery, and Signaling.
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.
authors.affiliation: Department of Pathophysiology, Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine , Shanghai, 200025, China.|Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, National Cancer Institute , Frederick, Maryland 21702, United States.
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Lu
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, National Cancer Institute , Frederick, Maryland 21702, United States.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.forename: Serena
authors.initials: S
authors.lastname: Muratcioglu
authors.forename: Attila
authors.initials: A
authors.lastname: Gursoy
authors.forename: Ozlem
authors.initials: O
authors.lastname: Keskin
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, National Cancer Institute , Frederick, Maryland 21702, United States.|Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Sackler Institute of Molecular Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: Department of Pathophysiology, Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine , Shanghai, 200025, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000494:Allosteric Regulation; D020134:Catalytic Domain; D006160:Guanosine Triphosphate / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006160:Guanosine Triphosphate; D018631:ras Proteins