GPCR activation mechanisms across classes and macro/microscales

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GPCR activation mechanisms across classes and macro/microscales. / Hauser, Alexander S.; Kooistra, Albert J.; Munk, Christian; Heydenreich, Franziska M.; Veprintsev, Dmitry B.; Bouvier, Michel; Babu, M. Madan; Gloriam, David E.

In: Nature Structural and Molecular Biology, Vol. 28, No. 11, 2021, p. 879-888.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Hauser, AS, Kooistra, AJ, Munk, C, Heydenreich, FM, Veprintsev, DB, Bouvier, M, Babu, MM & Gloriam, DE 2021, 'GPCR activation mechanisms across classes and macro/microscales', Nature Structural and Molecular Biology, vol. 28, no. 11, pp. 879-888. https://doi.org/10.1038/s41594-021-00674-7

APA

Hauser, A. S., Kooistra, A. J., Munk, C., Heydenreich, F. M., Veprintsev, D. B., Bouvier, M., Babu, M. M., & Gloriam, D. E. (2021). GPCR activation mechanisms across classes and macro/microscales. Nature Structural and Molecular Biology, 28(11), 879-888. https://doi.org/10.1038/s41594-021-00674-7

Vancouver

Hauser AS, Kooistra AJ, Munk C, Heydenreich FM, Veprintsev DB, Bouvier M et al. GPCR activation mechanisms across classes and macro/microscales. Nature Structural and Molecular Biology. 2021;28(11):879-888. https://doi.org/10.1038/s41594-021-00674-7

Author

Hauser, Alexander S. ; Kooistra, Albert J. ; Munk, Christian ; Heydenreich, Franziska M. ; Veprintsev, Dmitry B. ; Bouvier, Michel ; Babu, M. Madan ; Gloriam, David E. / GPCR activation mechanisms across classes and macro/microscales. In: Nature Structural and Molecular Biology. 2021 ; Vol. 28, No. 11. pp. 879-888.

Bibtex

@article{e405a1ea229840e3abb8e70367844679,
title = "GPCR activation mechanisms across classes and macro/microscales",
abstract = "Two-thirds of human hormones and one-third of clinical drugs activate ~350 G-protein-coupled receptors (GPCR) belonging to four classes: A, B1, C and F. Whereas a model of activation has been described for class A, very little is known about the activation of the other classes, which differ by being activated by endogenous ligands bound mainly or entirely extracellularly. Here we show that, although they use the same structural scaffold and share several {\textquoteleft}helix macroswitches{\textquoteright}, the GPCR classes differ in their {\textquoteleft}residue microswitch{\textquoteright} positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and methods for contact analysis applicable for any functional determinants. This provides a superfamily residue-level rationale for conformational selection and allosteric communication by ligands and G proteins, laying the foundation for receptor-function studies and drugs with the desired modality.",
author = "Hauser, {Alexander S.} and Kooistra, {Albert J.} and Christian Munk and Heydenreich, {Franziska M.} and Veprintsev, {Dmitry B.} and Michel Bouvier and Babu, {M. Madan} and Gloriam, {David E.}",
note = "Funding Information: This work was supported by the Lundbeck Foundation (grants R163-2013-16327 and R218-2016-1266), the Funding Information: Novo Nordisk Foundation (grant NNF18OC0031226) and Independent Research Fund Denmark | Natural Funding Information: Sciences (grant 8021-00173B) to D.E.G and by the American Lebanese Syrian Associated Charities (ALSAC). Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
doi = "10.1038/s41594-021-00674-7",
language = "English",
volume = "28",
pages = "879--888",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "nature publishing group",
number = "11",

}

RIS

TY - JOUR

T1 - GPCR activation mechanisms across classes and macro/microscales

AU - Hauser, Alexander S.

AU - Kooistra, Albert J.

AU - Munk, Christian

AU - Heydenreich, Franziska M.

AU - Veprintsev, Dmitry B.

AU - Bouvier, Michel

AU - Babu, M. Madan

AU - Gloriam, David E.

N1 - Funding Information: This work was supported by the Lundbeck Foundation (grants R163-2013-16327 and R218-2016-1266), the Funding Information: Novo Nordisk Foundation (grant NNF18OC0031226) and Independent Research Fund Denmark | Natural Funding Information: Sciences (grant 8021-00173B) to D.E.G and by the American Lebanese Syrian Associated Charities (ALSAC). Publisher Copyright: © 2021, The Author(s).

PY - 2021

Y1 - 2021

N2 - Two-thirds of human hormones and one-third of clinical drugs activate ~350 G-protein-coupled receptors (GPCR) belonging to four classes: A, B1, C and F. Whereas a model of activation has been described for class A, very little is known about the activation of the other classes, which differ by being activated by endogenous ligands bound mainly or entirely extracellularly. Here we show that, although they use the same structural scaffold and share several ‘helix macroswitches’, the GPCR classes differ in their ‘residue microswitch’ positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and methods for contact analysis applicable for any functional determinants. This provides a superfamily residue-level rationale for conformational selection and allosteric communication by ligands and G proteins, laying the foundation for receptor-function studies and drugs with the desired modality.

AB - Two-thirds of human hormones and one-third of clinical drugs activate ~350 G-protein-coupled receptors (GPCR) belonging to four classes: A, B1, C and F. Whereas a model of activation has been described for class A, very little is known about the activation of the other classes, which differ by being activated by endogenous ligands bound mainly or entirely extracellularly. Here we show that, although they use the same structural scaffold and share several ‘helix macroswitches’, the GPCR classes differ in their ‘residue microswitch’ positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and methods for contact analysis applicable for any functional determinants. This provides a superfamily residue-level rationale for conformational selection and allosteric communication by ligands and G proteins, laying the foundation for receptor-function studies and drugs with the desired modality.

U2 - 10.1038/s41594-021-00674-7

DO - 10.1038/s41594-021-00674-7

M3 - Journal article

C2 - 34759375

AN - SCOPUS:85118874763

VL - 28

SP - 879

EP - 888

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

SN - 1545-9993

IS - 11

ER -

ID: 285938909