Structure of a transient intermediate for GTP hydrolysis by ras

Structure
Bradley FordNicolas Nassar

Abstract

The flexibility of the conserved 57DTAGQ61 motif is essential for Ras proper cycling in response to growth factors. Here, we increase the flexibility of the 57DTAGQ61 motif by mutating Gln61 to Gly. The crystal structure of the RasQ61G mutant reveals a new conformation of switch 2 that bears remarkable structural homology to an intermediate for GTP hydrolysis revealed by targeted molecular dynamics simulations. The mutation increased retention of GTP and inhibited Ras binding to the catalytic site, but not to the distal site of Sos. Most importantly, the thermodynamics of RafRBD binding to Ras are altered even though the structure of switch 1 is not affected by the mutation. Our results suggest that interplay and transmission of structural information between the switch regions are important factors for Ras function. They propose that initiation of GTP hydrolysis sets off the separation of the Ras/effector complex even before the GDP conformation is reached.

References

Oct 29, 1997·Proceedings of the National Academy of Sciences of the United States of America·J Ma, M Karplus
Aug 1, 1998·The Journal of Biological Chemistry·A B Vojtek, C J Der
Apr 10, 1999·The Journal of Biological Chemistry·N van den BergheA Wittinghofer
Jan 3, 2001·Acta Crystallographica. Section D, Biological Crystallography·M D WinnG N Murshudov
Apr 9, 2001·The Journal of Biological Chemistry·M G RudolphC Herrmann
Sep 6, 2002·Proceedings of the National Academy of Sciences of the United States of America·Brian E HallNicolas Nassar
Sep 28, 2002·Acta Crystallographica. Section D, Biological Crystallography·Thomas R Schneider, George M Sheldrick
Jan 2, 2003·Nature Reviews. Cancer·Julian Downward
Apr 26, 2003·Acta Crystallographica. Section A, Foundations of Crystallography·Zbyszek OtwinowskiWladek Minor
Mar 3, 2004·Acta Crystallographica. Section D, Biological Crystallography·Laurent C StoroniRandy J Read
Jul 9, 2004·Journal of Molecular Biology·Christina KielChristian Herrmann
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson

❮ Previous
Next ❯

Citations

Feb 6, 2010·Biochemistry·Nicolas NassarMiguel Garcia-Diaz
Feb 24, 2012·PLoS Computational Biology·Priyanka PrakashAlemayehu A Gorfe
Jan 28, 2016·Chemical Reviews·Shaoyong LuJian Zhang
Jan 15, 2013·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Dan LiErkang Wang
May 16, 2009·Journal of Computational Chemistry·B R BrooksM Karplus
Jan 18, 2008·Journal of Molecular Recognition : JMR·Oksana Okhrimenko, Ilian Jelesarov
Oct 17, 2015·Angewandte Chemie·Philipp M CrommHerbert Waldmann
Apr 8, 2015·Proteins·Abhijeet Kapoor, Alex Travesset
Aug 5, 2011·The Biochemical Journal·Simone Kunzelmann, Martin R Webb
Aug 3, 2013·Biochimica Et Biophysica Acta·Priyanka Prakash, Alemayehu A Gorfe
Aug 21, 2012·Bioorganic & Medicinal Chemistry Letters·Weiru WangJoachim Rudolph
Oct 2, 2014·PloS One·Abhijeet Kapoor, Alex Travesset
May 13, 2017·Proteins·Abdallah Sayyed-AhmadAlemayehu A Gorfe
Dec 5, 2017·Acta Crystallographica. Section D, Structural Biology·Shenyuan XuMichael A Kennedy
Sep 16, 2020·Physical Chemistry Chemical Physics : PCCP·Jianzhong ChenWeiliang Zhu
Jun 21, 2017·The Journal of Biological Chemistry·Christian W JohnsonCarla Mattos
Nov 4, 2009·Biochemistry·Bradley FordNicolas Nassar
Feb 25, 2015·Analytical Chemistry·Kari KopraHarri Härmä

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Proceedings of the National Academy of Sciences of the United States of America
Brian E HallNicolas Nassar
Proceedings of the National Academy of Sciences of the United States of America
J Ma, M Karplus
© 2021 Meta ULC. All rights reserved