Aarhus University Seal / Aarhus Universitets segl

Structural insights into the inhibition of glycine reuptake

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Standard

Structural insights into the inhibition of glycine reuptake. / Shahsavar, Azadeh; Stohler, Peter; Bourenkov, Gleb; Zimmermann, Iwan ; Siegrist, Martin ; Guba, Wolfgang; Pinard, Emmanuel ; Sinning, Steffen; Seeger, Markus A.; Schneider, Thomas R.; Dawson, Roger J. P.; Nissen, Poul.

In: Nature, Vol. 591, 03.2021, p. 677-681.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Shahsavar, A, Stohler, P, Bourenkov, G, Zimmermann, I, Siegrist, M, Guba, W, Pinard, E, Sinning, S, Seeger, MA, Schneider, TR, Dawson, RJP & Nissen, P 2021, 'Structural insights into the inhibition of glycine reuptake', Nature, vol. 591, pp. 677-681. https://doi.org/10.1038/s41586-021-03274-z

APA

Shahsavar, A., Stohler, P., Bourenkov, G., Zimmermann, I., Siegrist, M., Guba, W., Pinard, E., Sinning, S., Seeger, M. A., Schneider, T. R., Dawson, R. J. P., & Nissen, P. (2021). Structural insights into the inhibition of glycine reuptake. Nature, 591, 677-681. https://doi.org/10.1038/s41586-021-03274-z

CBE

Shahsavar A, Stohler P, Bourenkov G, Zimmermann I, Siegrist M, Guba W, Pinard E, Sinning S, Seeger MA, Schneider TR, Dawson RJP, Nissen P. 2021. Structural insights into the inhibition of glycine reuptake. Nature. 591:677-681. https://doi.org/10.1038/s41586-021-03274-z

MLA

Vancouver

Shahsavar A, Stohler P, Bourenkov G, Zimmermann I, Siegrist M, Guba W et al. Structural insights into the inhibition of glycine reuptake. Nature. 2021 Mar;591:677-681. https://doi.org/10.1038/s41586-021-03274-z

Author

Shahsavar, Azadeh ; Stohler, Peter ; Bourenkov, Gleb ; Zimmermann, Iwan ; Siegrist, Martin ; Guba, Wolfgang ; Pinard, Emmanuel ; Sinning, Steffen ; Seeger, Markus A. ; Schneider, Thomas R. ; Dawson, Roger J. P. ; Nissen, Poul. / Structural insights into the inhibition of glycine reuptake. In: Nature. 2021 ; Vol. 591. pp. 677-681.

Bibtex

@article{83cad32c46a74f32917c207ffdee43fe,
title = "Structural insights into the inhibition of glycine reuptake",
abstract = "The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine1,2,3. Inhibition of GlyT1 prolongs neurotransmitter signalling, and has long been a key strategy in the development of therapies for a broad range of disorders of the central nervous system, including schizophrenia and cognitive impairments4. Here, using a synthetic single-domain antibody (sybody) and serial synchrotron crystallography, we have determined the structure of GlyT1 in complex with a benzoylpiperazine chemotype inhibitor at 3.4 {\AA} resolution. We find that the inhibitor locks GlyT1 in an inward-open conformation and binds at the intracellular gate of the release pathway, overlapping with the glycine-release site. The inhibitor is likely to reach GlyT1 from the cytoplasmic leaflet of the plasma membrane. Our results define the mechanism of inhibition and enable the rational design of new, clinically efficacious GlyT1 inhibitors.",
author = "Azadeh Shahsavar and Peter Stohler and Gleb Bourenkov and Iwan Zimmermann and Martin Siegrist and Wolfgang Guba and Emmanuel Pinard and Steffen Sinning and Seeger, {Markus A.} and Schneider, {Thomas R.} and Dawson, {Roger J. P.} and Poul Nissen",
year = "2021",
month = mar,
doi = "10.1038/s41586-021-03274-z",
language = "English",
volume = "591",
pages = "677--681",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Structural insights into the inhibition of glycine reuptake

AU - Shahsavar, Azadeh

AU - Stohler, Peter

AU - Bourenkov, Gleb

AU - Zimmermann, Iwan

AU - Siegrist, Martin

AU - Guba, Wolfgang

AU - Pinard, Emmanuel

AU - Sinning, Steffen

AU - Seeger, Markus A.

AU - Schneider, Thomas R.

AU - Dawson, Roger J. P.

AU - Nissen, Poul

PY - 2021/3

Y1 - 2021/3

N2 - The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine1,2,3. Inhibition of GlyT1 prolongs neurotransmitter signalling, and has long been a key strategy in the development of therapies for a broad range of disorders of the central nervous system, including schizophrenia and cognitive impairments4. Here, using a synthetic single-domain antibody (sybody) and serial synchrotron crystallography, we have determined the structure of GlyT1 in complex with a benzoylpiperazine chemotype inhibitor at 3.4 Å resolution. We find that the inhibitor locks GlyT1 in an inward-open conformation and binds at the intracellular gate of the release pathway, overlapping with the glycine-release site. The inhibitor is likely to reach GlyT1 from the cytoplasmic leaflet of the plasma membrane. Our results define the mechanism of inhibition and enable the rational design of new, clinically efficacious GlyT1 inhibitors.

AB - The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine1,2,3. Inhibition of GlyT1 prolongs neurotransmitter signalling, and has long been a key strategy in the development of therapies for a broad range of disorders of the central nervous system, including schizophrenia and cognitive impairments4. Here, using a synthetic single-domain antibody (sybody) and serial synchrotron crystallography, we have determined the structure of GlyT1 in complex with a benzoylpiperazine chemotype inhibitor at 3.4 Å resolution. We find that the inhibitor locks GlyT1 in an inward-open conformation and binds at the intracellular gate of the release pathway, overlapping with the glycine-release site. The inhibitor is likely to reach GlyT1 from the cytoplasmic leaflet of the plasma membrane. Our results define the mechanism of inhibition and enable the rational design of new, clinically efficacious GlyT1 inhibitors.

U2 - 10.1038/s41586-021-03274-z

DO - 10.1038/s41586-021-03274-z

M3 - Journal article

C2 - 33658720

VL - 591

SP - 677

EP - 681

JO - Nature

JF - Nature

SN - 0028-0836

ER -