Structural insights into the inhibition of glycine reuptake

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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.

I: Nature, Bind 591, 2021, s. 677–681.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

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, bind 591, s. 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

Vancouver

Shahsavar A, Stohler P, Bourenkov G, Zimmermann I, Siegrist M, Guba W o.a. Structural insights into the inhibition of glycine reuptake. Nature. 2021;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. I: Nature. 2021 ; Bind 591. s. 677–681.

Bibtex

@article{7d2247900578498eb7582503b188debe,
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",
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

Y1 - 2021

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

VL - 591

SP - 677

EP - 681

JO - Nature

JF - Nature

SN - 0028-0836

ER -

ID: 339170986