Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action

ELife
Jonathan B SteinmanTarun M Kapoor

Abstract

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has in part been limited by low potency. Moreover, suboptimal chemical properties, such as the potential to isomerize, have hindered efforts to improve ciliobrevins. Here, we characterized the structure of ciliobrevins and designed conformationally constrained isosteres. These studies identified dynapyrazoles, inhibitors more potent than ciliobrevins. At single-digit micromolar concentrations dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Further, we find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles strongly block only microtubule-stimulated activity. Together, our studies suggest that chemical-structure-based analyses can lead to inhibitors with improved properties and distinct modes of inhibition.

References

Apr 28, 1978·Biochemical and Biophysical Research Communications·T KobayashiM Flavin
May 1, 1978·Proceedings of the National Academy of Sciences of the United States of America·I R GibbonsW J Tang
Sep 1, 1988·The Journal of Cell Biology·H S ShpetnerR B Vallee
Feb 1, 1981·Proceedings of the National Academy of Sciences of the United States of America·P BouchardC W Bardin
Oct 29, 1997·Proceedings of the National Academy of Sciences of the United States of America·C M Waterman-StorerE L Holzbaur
Aug 5, 1997·Chemical Reviews·Robert E. Babine, Steven L. Bender
Feb 21, 2002·The Journal of Cell Biology·Steven P GrossEric F Wieschaus
Oct 23, 2002·Proceedings of the National Academy of Sciences of the United States of America·James K ChenPhilip A Beachy
Jan 6, 2004·Journal of Neurobiology·Richard B ValleeLora E Barnhart
Mar 24, 2004·Journal of Structural Biology·Lakshminarayan M IyerL Aravind
Aug 3, 2005·Nature Reviews. Molecular Cell Biology·Phyllis I Hanson, Sidney W Whiteheart
Jan 13, 2006·Nature Chemical Biology·Michael A Lampson, Tarun M Kapoor
May 13, 2006·Annual Review of Biophysics and Biomolecular Structure·Jan P Erzberger, James M Berger
May 23, 2006·Nature Cell Biology·Jennifer L RossErika L F Holzbaur
Oct 4, 2007·Proceedings of the National Academy of Sciences of the United States of America·Kenji ImamulaKazuo Sutoh
Dec 25, 2007·Acta Crystallographica. Section A, Foundations of Crystallography·George M Sheldrick
Sep 12, 2008·The EMBO Journal·Masami YamadaShinji Hirotsune
Jan 28, 2009·Acta Crystallographica. Section D, Biological Crystallography·Anthony L Spek
Jun 23, 2009·Bioorganic & Medicinal Chemistry Letters·Federica OrvietoEster Muraglia
Aug 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Joel M HymanJames K Chen
Dec 30, 2009·The Journal of Cell Biology·Shabeen AllyVladimir I Gelfand
Apr 17, 2010·Nature Reviews. Genetics·Sarah C Goetz, Kathryn V Anderson
Nov 26, 2010·Nature Cell Biology·Kassandra M Ori-McKenneyRichard B Vallee
Mar 24, 2011·Nature Reviews. Molecular Cell Biology·Hiroaki Ishikawa, Wallace F Marshall
Jul 9, 2011·Biochimica Et Biophysica Acta·Tania A Baker, Robert T Sauer
Sep 23, 2011·Biochemical Society Transactions·Victoria J Allan
Feb 22, 2012·Bioorganic & Medicinal Chemistry Letters·Joerg BusseniusKenneth D Rice
Mar 20, 2012·Nature·Ari J FirestoneJames K Chen
Apr 3, 2012·Nature Chemical Biology·Iana M SerafimovaJack Taunton
Jun 30, 2012·Nature Methods·Johannes SchindelinAlbert Cardona
Aug 7, 2012·Molecular & Cellular Proteomics : MCP·Amelia C PetersonJoshua J Coon
Oct 3, 2012·The Journal of Cell Biology·Benjamin D EngelWallace F Marshall
Mar 21, 2013·Current Opinion in Cell Biology·Kari BarlanVladimir I Gelfand
Mar 26, 2013·Journal of Cell Science·Andrew P Carter
Jul 3, 2013·Proceedings of the National Academy of Sciences of the United States of America·Xin LiuMorgan Huse
Nov 25, 2014·Cell·Gira BhabhaRonald D Vale
Dec 4, 2014·Nature·Helgo SchmidtAndrew P Carter
Dec 9, 2014·Nature Structural & Molecular Biology·Mark A DeWittAhmet Yildiz
Feb 12, 2015·Nature Communications·Matthew P NicholasArne Gennerich

❮ Previous
Next ❯

Citations

Nov 15, 2017·Science Advances·Ping LiuKen Jacobson
Oct 3, 2020·Expert Opinion on Drug Discovery·Christopher O Dusek, M Kyle Hadden
Aug 2, 2018·Biochemical Society Transactions·Anthony J Roberts
Jan 27, 2021·The Journal of Cell Biology·Michal WieczorekTarun M Kapoor
May 21, 2021·Cell Chemical Biology·Cristina C SantarossaTarun M Kapoor
Jul 25, 2021·International Journal of Molecular Sciences·Sayi'Mone Tati, Laleh Alisaraie

❮ Previous
Next ❯

Datasets Mentioned

BETA
1510769

Methods Mentioned

BETA
x-ray crystallography
X-ray
NMR
Gel filtration
motility assay
size exclusion chromatography
column chromatography
silica-gel column chromatography
ion exchange chromatography
Assay

Software Mentioned

ORTEP
KymographDirect
FIJI
Diatrack
Mascot
PLATON
KymographClear
Kymograph
ProteomeDiscoverer
ClustalW

Related Concepts

Related Feeds

Aortic Aneurysm

An aortic aneurysm is the weakening and bulging of the blood vessel wall in the aorta. This causes dilatation of the aorta, which is usually asymptomatic but carries the risk of rupture and hemorrhage. Find the latest research on aortic aneurysms here.

Aneurysm

Aneurysms are outward distensions or bulges that occurs in a weakened wall of blood vessels. Discover the latest research on aneurysms here.