Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil

Structure
Hiroto YamaguchiToshio Hakoshima

Abstract

Rho-kinase is a key regulator of cytoskeletal events and a promising drug target in the treatment of vascular diseases and neurological disorders. Unlike other protein kinases, Rho-kinase requires both N- and C-terminal extension segments outside the kinase domain for activity, although the details of this requirement have been elusive. The crystal structure of an active Rho-kinase fragment containing the kinase domain and both the extensions revealed a head-to-head homodimer through the N-terminal extension forming a helix bundle that structurally integrates the C-terminal extension. This structural organization enables binding of the C-terminal hydrophobic motif to the N-terminal lobe, which defines the correct disposition of helix alphaC that is important for the catalytic activity. The bound inhibitor fasudil significantly alters the conformation and, consequently, the mode of interaction with the catalytic cleft that contains local structural changes. Thus, both kinase and drug conformational pliability and stability confer selectivity.

References

Aug 23, 1996·The Journal of Biological Chemistry·M AmanoK Kaibuchi
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Mar 25, 1999·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Jul 27, 1999·Current Biology : CB·R T Peterson, S L Schreiber
Aug 24, 1999·Pharmacology & Therapeutics·N Ono-SaitoH Hidaka
Nov 5, 1999·The Journal of Biological Chemistry·M AmanoK Kaibuchi
Jun 29, 2000·Annual Review of Biochemistry·K KaibuchiM Amano
May 23, 2002·Cell·Morgan Huse, John Kuriyan
Dec 13, 2002·Nature·Sandrine Etienne-Manneville, Alan Hall
Dec 24, 2002·The Biochemical Journal·Alexandra C Newton
Dec 31, 2002·Current Opinion in Structural Biology·Laurence H Pearl, David Barford
Mar 26, 2003·Cell·Bhushan NagarJohn Kuriyan
Jun 5, 2003·Nature Reviews. Molecular Cell Biology·Kirsi Riento, Anne J Ridley
Sep 5, 2003·The Journal of Biological Chemistry·Toshiyuki ShimizuToshio Hakoshima
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
May 3, 2005·Nature Reviews. Drug Discovery·Bernhard K MuellerNicole Teusch
Aug 9, 2005·Expert Opinion on Therapeutic Targets·Erding Hu, Dennis Lee

❮ Previous
Next ❯

Citations

Apr 2, 2014·Bioorganic & Medicinal Chemistry Letters·Hwang-Hsing ChenKeith D Combrink
Feb 21, 2014·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Mathieu Unbekandt, Michael F Olson
Apr 10, 2012·Annual Review of Biochemistry·Jane A EndicottLouise N Johnson
Aug 13, 2014·Proceedings of the National Academy of Sciences of the United States of America·Rachel S KadzikEdward E Morrisey
Aug 11, 2010·The Journal of Clinical Investigation·Partha S BiswasAlessandra B Pernis
Oct 29, 2011·Stroke; a Journal of Cerebral Circulation·David A McDonaldIssam A Awad
Feb 26, 2013·The Journal of Clinical Investigation·Yong ZhouVictor J Thannickal
Oct 24, 2013·Journal of Molecular Graphics & Modelling·John W CraftJames M Briggs
Jul 25, 2007·Journal of Computer-aided Molecular Design·Ki Hwan Kim
Apr 17, 2008·Journal of Computer-aided Molecular Design·Keigo Gohda, Toshio Hakoshima
Dec 15, 2011·Journal of Computer-aided Molecular Design·Rand ShahinMutasem O Taha
Oct 31, 2013·Journal of Biomedical Science·Hsiang-Hao ChuangHsiao-Hui Lee
May 26, 2010·Pharmaceuticals·Annegret Ulke-Lemée, Justin A MacDonald
Sep 4, 2012·Translational Research : the Journal of Laboratory and Clinical Medicine·Elif OguzAbdullah T Demiryürek
Jan 5, 2016·Archivum Immunologiae Et Therapiae Experimentalis·Lei WeiJianjian Shi
Jan 23, 2010·Experimental Parasitology·Judith H Waknine-GrinbergJacob Golenser
Feb 19, 2009·Biochemical and Biophysical Research Communications·Sylvester TumusiimeRebecca A Worthylake
Nov 8, 2008·Bioorganic & Medicinal Chemistry Letters·Yen Ting ChenYangbo Feng
Nov 11, 2008·Bioorganic & Medicinal Chemistry Letters·E Hampton SessionsYangbo Feng
Dec 2, 2015·Nature Communications·Linda TruebesteinThomas A Leonard
Dec 5, 2015·Frontiers in Pharmacology·Svenja HartmannSusanne Lutz
Nov 7, 2006·Current Opinion in Structural Biology·Matthew G GoldDavid Komander
Oct 24, 2008·The EMBO Journal·David KomanderDavid Barford
Mar 25, 2009·Protein Science : a Publication of the Protein Society·Jonathan M ElkinsStefan Knapp
Jun 16, 2011·Development, Growth & Differentiation·Beatriz Aguirre-ArmentaJesús García-Soto
Oct 22, 2015·Journal of Medicinal Chemistry·Yangbo FengRongshi Li
Nov 7, 2006·Bioorganic & Medicinal Chemistry·Masayuki IwakuboHiroshi Iijima
Apr 16, 2016·Bioorganic & Medicinal Chemistry Letters·Surmil Shah, Jignasa Savjani
May 24, 2015·Biochimica Et Biophysica Acta·Osman A GaniRichard A Engh
Sep 11, 2009·The Biochemical Journal·R Jeremy NicholsDario R Alessi
Jun 24, 2015·The Journal of Cell Biology·Mutsuki AmanoKozo Kaibuchi
May 14, 2010·Bioorganic & Medicinal Chemistry Letters·Frank WuCharles L Cywin
Nov 12, 2013·European Journal of Medicinal Chemistry·Ronggui GuanRongbiao Pi
Apr 14, 2016·Small GTPases·Linda TruebesteinThomas A Leonard

❮ 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

Protein Science : a Publication of the Protein Society
Jonathan M ElkinsStefan Knapp
The Journal of Biological Chemistry
Radovan DvorskyMohammad Reza Ahmadian
© 2021 Meta ULC. All rights reserved