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Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation

View ORCID ProfileMathieu Botte, View ORCID ProfileAlexander K. C. Ulrich, View ORCID ProfileRicardo Adaixo, View ORCID ProfileDavid Gnutt, View ORCID ProfileAndreas Brockmann, View ORCID ProfileDenis Bucher, View ORCID ProfileMohamed Chami, View ORCID ProfileNicolas Bocquet, Ulrich Ebbinghaus-Kintscher, Vera Puetter, Andreas Becker, Ursula Egner, View ORCID ProfileHenning Stahlberg, View ORCID ProfileMichael Hennig, View ORCID ProfileSimon J. Holton
doi: https://doi.org/10.1101/2020.10.13.334797
Mathieu Botte
1leadXpro AG, PARK innovAARE, 5234 Villigen, Switzerland
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Alexander K. C. Ulrich
2Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
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  • ORCID record for Alexander K. C. Ulrich
Ricardo Adaixo
3Centre for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Basel, Switzerland
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David Gnutt
4Bayer AG, Research & Development, Pharmaceuticals, 42113 Wuppertal, Germany
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Andreas Brockmann
5Bayer AG, Research & Development, Crop Science, 40789 Monheim, Germany
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Denis Bucher
1leadXpro AG, PARK innovAARE, 5234 Villigen, Switzerland
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Mohamed Chami
3Centre for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Basel, Switzerland
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Nicolas Bocquet
1leadXpro AG, PARK innovAARE, 5234 Villigen, Switzerland
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Ulrich Ebbinghaus-Kintscher
5Bayer AG, Research & Development, Crop Science, 40789 Monheim, Germany
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Vera Puetter
2Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
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Andreas Becker
2Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
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Ursula Egner
2Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
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Henning Stahlberg
3Centre for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Basel, Switzerland
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  • ORCID record for Henning Stahlberg
Michael Hennig
1leadXpro AG, PARK innovAARE, 5234 Villigen, Switzerland
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  • For correspondence: simon.holton@nuvisan.com
Simon J. Holton
2Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
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  • For correspondence: simon.holton@nuvisan.com
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ABSTRACT

The human transient receptor potential vanilloid 4 (hTRPV4) ion channel plays a critical role in a variety of biological processes. Whilst the activation of hTRPV4 gating properties has been reported for a broad spectrum of stimuli, including synthetic 4α-phorbols, the molecular basis of the activation is poorly understood. Here we report the novel cryo-EM structure of the hTRPV4 determined in the presence of the archetypical phorbol acid agonist, 4α-PDD. Complementary mutagenesis experiments support the EM-identified binding site as well as allowing rationalization of disruptive mutants located outside of the 4α-PDD binding site. This work represents the first structural information of hTRPV4 in a ligand-induced open conformation. Together, our data reveal the underlying molecular mechanisms resulting in the opening of the central pore and ion-channel activation and provide a structural template for designing inhibitors targeting the open-state conformation of hTRPV4.

Competing Interest Statement

The authors declare the following competing financial interest(s): A.K.C.U., U.E., D.G., V.P., U.E-K., A.B., A.B. and S.J.H. are / were employees of Bayer AG and may have additional stock options. M.B., N.B., D.B. and M.H. are employees of leadXpro AG and may have additional stock options. The other authors declare that no competing interests exist.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 13, 2020.
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Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation
Mathieu Botte, Alexander K. C. Ulrich, Ricardo Adaixo, David Gnutt, Andreas Brockmann, Denis Bucher, Mohamed Chami, Nicolas Bocquet, Ulrich Ebbinghaus-Kintscher, Vera Puetter, Andreas Becker, Ursula Egner, Henning Stahlberg, Michael Hennig, Simon J. Holton
bioRxiv 2020.10.13.334797; doi: https://doi.org/10.1101/2020.10.13.334797
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Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation
Mathieu Botte, Alexander K. C. Ulrich, Ricardo Adaixo, David Gnutt, Andreas Brockmann, Denis Bucher, Mohamed Chami, Nicolas Bocquet, Ulrich Ebbinghaus-Kintscher, Vera Puetter, Andreas Becker, Ursula Egner, Henning Stahlberg, Michael Hennig, Simon J. Holton
bioRxiv 2020.10.13.334797; doi: https://doi.org/10.1101/2020.10.13.334797

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