Structural Design and Analysis of the RHOA-ARHGEF1 Binding Mode: Challenges and Applications for Protein-Protein Interface Prediction.

Frontiers in Molecular Biosciences
Ennys GheyoucheStéphane Téletchéa

Abstract

The interaction between two proteins may involve local movements, such as small side-chains re-positioning or more global allosteric movements, such as domain rearrangement. We studied how one can build a precise and detailed protein-protein interface using existing protein-protein docking methods, and how it can be possible to enhance the initial structures using molecular dynamics simulations and data-driven human inspection. We present how this strategy was applied to the modeling of RHOA-ARHGEF1 interaction using similar complexes of RHOA bound to other members of the Rho guanine nucleotide exchange factor family for comparative assessment. In parallel, a more crude approach based on structural superimposition and molecular replacement was also assessed. Both models were then successfully refined using molecular dynamics simulations leading to protein structures where the major data from scientific literature could be recovered. We expect that the detailed strategy used in this work will prove useful for other protein-protein interface design. The RHOA-ARHGEF1 interface modeled here will be extremely useful for the design of inhibitors targeting this protein-protein interaction (PPI).

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Sep 23, 1997·Journal of Molecular Biology·H A GabbM J Sternberg
May 23, 1998·The Journal of Biological Chemistry·K IharaT Hakoshima
Jan 11, 2000·Nucleic Acids Research·S BalajiN Srinivasan
Feb 13, 2002·Current Opinion in Structural Biology·Graham R Smith, Michael J E Sternberg
Mar 26, 2002·FEBS Letters·Gregory R Hoffman, Richard A Cerione
Nov 25, 2003·Nature Structural Biology·Helen BermanHaruki Nakamura
Feb 12, 2004·Science's STKE : Signal Transduction Knowledge Environment·Tanja KortemmeDavid Baker
Aug 8, 2007·Journal of Molecular Biology·Evgeny Krissinel, Kim Henrick
Oct 9, 2007·Proteins·Marc F LensinkShoshana J Wodak
Jan 20, 2009·Bioinformatics·Andrew M WaterhouseGeoffrey J Barton
May 8, 2009·Journal of Computational Chemistry·Evgeny Krissinel
Dec 19, 2009·The Journal of Biological Chemistry·Geneviève M C Gasmi-SeabrookMitsuhiko Ikura
Apr 22, 2010·Proteins·Kresten Lindorff-LarsenDavid E Shaw
Sep 3, 2010·Nature Reviews. Cardiology·Gervaise Loirand, Pierre Pacaud
Nov 9, 2010·Proteins·Srinivas RamachandranNikolay V Dokholyan
Nov 11, 2010·Protein Science : a Publication of the Protein Society·Zhe ChenPaul C Sternweis
Jul 20, 2011·Nature Chemical Biology·Jacqueline Cherfils, Mahel Zeghouf
Aug 6, 2011·The Journal of Biological Chemistry·Jakub A BielnickiZygmunt S Derewenda
Jul 25, 2012·BMC Research Notes·Alan W Sousa da Silva, Wim F Vranken
Jan 11, 2013·Physiological Reviews·Jacqueline Cherfils, Mahel Zeghouf
Feb 13, 2013·Nature Methods·Roberto MoscaPatrick Aloy
Mar 28, 2013·Molecular BioSystems·Anshul Sukhwal, Ramanathan Sowdhamini
May 11, 2013·Bioinformatics·Brian Jiménez-GarcíaJuan Fernández-Recio
Nov 25, 2014·Cell·Thomas RollandMarc Vidal
Apr 15, 2015·Hypertension·Maria Luigia CarboneGervaise Loirand
Sep 28, 2015·Journal of Molecular Biology·G C P van ZundertA M J J Bonvin
Oct 1, 2015·Pharmacological Reviews·Gervaise Loirand
Oct 23, 2015·Handbook of Experimental Pharmacology·C Ottmann
Oct 30, 2015·Future Medicinal Chemistry·Malgorzata Skwarczynska, Christian Ottmann
Mar 17, 2016·Database : the Journal of Biological Databases and Curation·Marie-Jeanne BassePhilippe Roche
Jan 13, 2017·Nature Protocols·Dima KozakovSandor Vajda
Jun 6, 2017·Journal of Computational Chemistry·Jean-Baptiste ChéronSébastien Fiorucci
Jul 19, 2017·International Journal of Molecular Sciences·Jinjian JiangBing Wang
Oct 27, 2017·Protein Science : a Publication of the Protein Society·Christopher J WilliamsDavid C Richardson
Nov 12, 2017·Proteins·Marc F LensinkShoshana J Wodak

❮ Previous
Next ❯

Software Mentioned

MolProbity
acpype
MDplot
GROMACS SAS
HADDOCK
Chiron
complexT
CAPRI
PyMOL
ATTRACT

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.