Biochemical suppression of small-molecule inhibitors: a strategy to identify inhibitor targets and signaling pathway components.

Chemistry & Biology
Jeffrey R PetersonMarc W Kirschner

Abstract

Identification of small-molecule targets remains an important challenge for chemical genetics. We report an approach for target identification and protein discovery based on functional suppression of chemical inhibition in vitro. We discovered pirl1, an inhibitor of actin assembly, in a screen conducted with cytoplasmic extracts. Pirl1 was used to partially inhibit actin assembly in the same assay, and concentrated biochemical fractions of cytoplasmic extracts were added to find activities that suppressed pirl1 inhibition. Two activities were detected, separately purified, and identified as Arp2/3 complex and Cdc42/RhoGDI complex, both known regulators of actin assembly. We show that pirl1 directly inhibits activation of Cdc42/RhoGDI, but that Arp2/3 complex represents a downstream suppressor. This work introduces a general method for using low-micromolar chemical inhibitors to identify both inhibitor targets and other components of a signaling pathway.

References

Nov 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·M R BlockJ E Rothman
Nov 14, 1997·The Journal of Experimental Medicine·D CoxS Greenberg
Sep 13, 2001·Proceedings of the National Academy of Sciences of the United States of America·J R PetersonM W Kirschner
Apr 29, 2004·Chemistry & Biology·Sarah M WignallRebecca Heald
Jul 6, 2004·Nature Structural & Molecular Biology·Jeffrey R PetersonMichael K Rosen
Dec 8, 2004·Combinatorial Chemistry & High Throughput Screening·Gregory P Tochtrop, Randall W King
Jan 25, 2005·Chemistry & Biology·Hendrik LueschFrantisek Supek
Feb 3, 2005·Nature Reviews. Molecular Cell Biology·Kent L RossmanJohn Sondek
Jan 13, 2006·Nature Chemical Biology·Henry E PelishTomas Kirchhausen

❮ Previous
Next ❯

Citations

May 9, 2006·Biochemical Pharmacology·Henry E PelishWayne I Lencer
Nov 1, 2008·American Journal of Physiology. Gastrointestinal and Liver Physiology·Irina MalyukovaOlga Kovbasnjuk
Sep 3, 2009·Molecular Cancer Therapeutics·Julien Viaud, Jeffrey R Peterson
Oct 5, 2013·The Journal of Clinical Investigation·Holly MartinReuben Kapur
Jul 1, 2007·HFSP Journal·Stefan FlorianThomas U Mayer
May 19, 2012·Reproduction : the Official Journal of the Society for the Study of Fertility·R Baltiérrez-HoyosE O Hernández-González
Jul 1, 2009·Expert Opinion on Drug Discovery·Chaitanya SaxenaJohn E Hale
Dec 23, 2015·Viruses·Thomas Swaine, Matthias T Dittmar
May 15, 2009·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Grant N Wheeler, André W Brändli
Feb 22, 2012·Genesis : the Journal of Genetics and Development·Grant N Wheeler, Karen J Liu
May 9, 2012·Cell Stem Cell·Maria Carolina FlorianHartmut Geiger
Sep 24, 2014·Neuro-oncology·Madhavi ChakravadhanulaRatan D Bhardwaj
Jan 27, 2015·Nature Cell Biology·Subramanian P RamanathanDaniel J Muller
Mar 19, 2016·Journal of Thrombosis and Haemostasis : JTH·A AntkowiakF Gaits-Iacovoni
Mar 30, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xing-Hua XiaoLi-Xia Xiong
Oct 22, 2013·Nature·Maria Carolina FlorianHartmut Geiger
Oct 17, 2015·Angewandte Chemie·Philipp M CrommHerbert Waldmann
Feb 19, 2013·Angewandte Chemie·Slava ZieglerHerbert Waldmann
Oct 6, 2007·Nature Reviews. Drug Discovery·Georg C TerstappenGiovanni Gaviraghi
Nov 17, 2011·Journal of Biomolecular Screening·Yong-Jun KwonNeil Emans
Oct 24, 2013·Médecine sciences : M/S·Renaud PrudentLaurence Lafanechère
Jul 1, 2020·Frontiers in Immunology·Heidi TackenbergTamás Laskay
Apr 24, 2020·Frontiers in Cell and Developmental Biology·Maria Del Mar MaldonadoSuranganie Dharmawardhane
Jun 10, 2017·Scientific Reports·Jorge LevicanOscar León
Nov 16, 2019·Journal of Cell Science·Florian WeeberTim Eiseler
Aug 13, 2014·Cancer Research·Ryotaro SakamoriNan Gao
Jun 3, 2018·Cancer Research·María Del Mar Maldonado, Suranganie Dharmawardhane
Jan 21, 2021·Cancer Metastasis Reviews·Carmen Ruggiero, Enzo Lalli
Feb 2, 2021·Science Advances·Amar J MajmundarFriedhelm Hildebrandt
Jan 26, 2020·Cancer Letters·Chun-Wen ZhengEn-Min Li
Mar 20, 2021·Médecine sciences : M/S·Preety ShabajeeJean-Philippe Stéphan
Apr 16, 2021·Science Translational Medicine·Samuel X ShiQiang Liu
Jul 6, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Guillermina M LuqueMariano G Buffone
Jan 1, 2014·ACS Chemical Biology·Daniel LängleDennis Schade

❮ 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

Current Opinion in Cell Biology
Nathaniel A Hathaway, R W King
Proceedings of the National Academy of Sciences of the United States of America
Julien HeuvinghCécile Sykes
© 2022 Meta ULC. All rights reserved