2.50
Hdl Handle:
http://hdl.handle.net/10547/227183
Title:
The distinct conformational dynamics of K-Ras and H-Ras A59G.
Authors:
Lukman, Suryani ( 0000-0002-8913-1343 ) ; Grant, Barry J.; Gorfe, Alemayehu A.; Grant, Guy H.; McCammon, J. Andrew
Abstract:
Ras proteins regulate signaling cascades crucial for cell proliferation and differentiation by switching between GTP- and GDP-bound conformations. Distinct Ras isoforms have unique physiological functions with individual isoforms associated with different cancers and developmental diseases. Given the small structural differences among isoforms and mutants, it is currently unclear how these functional differences and aberrant properties arise. Here we investigate whether the subtle differences among isoforms and mutants are associated with detectable dynamical differences. Extensive molecular dynamics simulations reveal that wild-type K-Ras and mutant H-Ras A59G are intrinsically more dynamic than wild-type H-Ras. The crucial switch 1 and switch 2 regions along with loop 3, helix 3, and loop 7 contribute to this enhanced flexibility. Removing the gamma-phosphate of the bound GTP from the structure of A59G led to a spontaneous GTP-to-GDP conformational transition in a 20-ns unbiased simulation. The switch 1 and 2 regions exhibit enhanced flexibility and correlated motion when compared to non-transitioning wild-type H-Ras over a similar timeframe. Correlated motions between loop 3 and helix 5 of wild-type H-Ras are absent in the mutant A59G reflecting the enhanced dynamics of the loop 3 region. Taken together with earlier findings, these results suggest the existence of a lower energetic barrier between GTP and GDP states of the mutant. Molecular dynamics simulations combined with principal component analysis of available Ras crystallographic structures can be used to discriminate ligand- and sequence-based dynamic perturbations with potential functional implications. Furthermore, the identification of specific conformations associated with distinct Ras isoforms and mutants provides useful information for efforts that attempt to selectively interfere with the aberrant functions of these species.
Affiliation:
University of Cambridge
Citation:
Suryani et al (2010) 'The distinct conformational dynamics of K-Ras and H-Ras A59G'. PLoS Comput. Biol. 6 (9): 1-9
Publisher:
Public Library of Science
Journal:
PLoS computational biology
Issue Date:
Sep-2010
URI:
http://hdl.handle.net/10547/227183
DOI:
10.1371/journal.pcbi.1000922
PubMed ID:
20838576
Type:
Article
Language:
en
ISSN:
1553-7358
Appears in Collections:
Cell and Cryobiology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorLukman, Suryanien_GB
dc.contributor.authorGrant, Barry J.en_GB
dc.contributor.authorGorfe, Alemayehu A.en_GB
dc.contributor.authorGrant, Guy H.en_GB
dc.contributor.authorMcCammon, J. Andrewen_GB
dc.date.accessioned2012-06-01T13:49:32Z-
dc.date.available2012-06-01T13:49:32Z-
dc.date.issued2010-09-
dc.identifier.citationSuryani et al (2010) 'The distinct conformational dynamics of K-Ras and H-Ras A59G'. PLoS Comput. Biol. 6 (9): 1-9en_GB
dc.identifier.issn1553-7358-
dc.identifier.pmid20838576-
dc.identifier.doi10.1371/journal.pcbi.1000922-
dc.identifier.urihttp://hdl.handle.net/10547/227183-
dc.description.abstractRas proteins regulate signaling cascades crucial for cell proliferation and differentiation by switching between GTP- and GDP-bound conformations. Distinct Ras isoforms have unique physiological functions with individual isoforms associated with different cancers and developmental diseases. Given the small structural differences among isoforms and mutants, it is currently unclear how these functional differences and aberrant properties arise. Here we investigate whether the subtle differences among isoforms and mutants are associated with detectable dynamical differences. Extensive molecular dynamics simulations reveal that wild-type K-Ras and mutant H-Ras A59G are intrinsically more dynamic than wild-type H-Ras. The crucial switch 1 and switch 2 regions along with loop 3, helix 3, and loop 7 contribute to this enhanced flexibility. Removing the gamma-phosphate of the bound GTP from the structure of A59G led to a spontaneous GTP-to-GDP conformational transition in a 20-ns unbiased simulation. The switch 1 and 2 regions exhibit enhanced flexibility and correlated motion when compared to non-transitioning wild-type H-Ras over a similar timeframe. Correlated motions between loop 3 and helix 5 of wild-type H-Ras are absent in the mutant A59G reflecting the enhanced dynamics of the loop 3 region. Taken together with earlier findings, these results suggest the existence of a lower energetic barrier between GTP and GDP states of the mutant. Molecular dynamics simulations combined with principal component analysis of available Ras crystallographic structures can be used to discriminate ligand- and sequence-based dynamic perturbations with potential functional implications. Furthermore, the identification of specific conformations associated with distinct Ras isoforms and mutants provides useful information for efforts that attempt to selectively interfere with the aberrant functions of these species.en_GB
dc.language.isoenen
dc.publisherPublic Library of Scienceen_GB
dc.rightsArchived with thanks to PLoS computational biologyen_GB
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subject.meshAmino Acid Sequence-
dc.subject.meshCatalytic Domain-
dc.subject.meshCrystallography-
dc.subject.meshGuanosine Diphosphate-
dc.subject.meshGuanosine Triphosphate-
dc.subject.meshHumans-
dc.subject.meshMolecular Dynamics Simulation-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshMutation-
dc.subject.meshPrincipal Component Analysis-
dc.subject.meshProtein Isoforms-
dc.subject.meshSignal Transduction-
dc.subject.meshras Proteins-
dc.titleThe distinct conformational dynamics of K-Ras and H-Ras A59G.en
dc.typeArticleen
dc.contributor.departmentUniversity of Cambridgeen_GB
dc.identifier.journalPLoS computational biologyen_GB

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