Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91

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

Standard

Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91. / Shenol, Aslihan; Lückmann, Michael; Trauelsen, Mette; Lambrughi, Matteo; Tiberti, Matteo; Papaleo, Elena; Frimurer, Thomas M; Schwartz, Thue W.

In: Molecular Cell, Vol. 84, No. 5, 2024, p. 955-966.e4.

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

Harvard

Shenol, A, Lückmann, M, Trauelsen, M, Lambrughi, M, Tiberti, M, Papaleo, E, Frimurer, TM & Schwartz, TW 2024, 'Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91', Molecular Cell, vol. 84, no. 5, pp. 955-966.e4. https://doi.org/10.1016/j.molcel.2024.01.011

APA

Shenol, A., Lückmann, M., Trauelsen, M., Lambrughi, M., Tiberti, M., Papaleo, E., Frimurer, T. M., & Schwartz, T. W. (2024). Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91. Molecular Cell, 84(5), 955-966.e4. https://doi.org/10.1016/j.molcel.2024.01.011

Vancouver

Shenol A, Lückmann M, Trauelsen M, Lambrughi M, Tiberti M, Papaleo E et al. Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91. Molecular Cell. 2024;84(5):955-966.e4. https://doi.org/10.1016/j.molcel.2024.01.011

Author

Shenol, Aslihan ; Lückmann, Michael ; Trauelsen, Mette ; Lambrughi, Matteo ; Tiberti, Matteo ; Papaleo, Elena ; Frimurer, Thomas M ; Schwartz, Thue W. / Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91. In: Molecular Cell. 2024 ; Vol. 84, No. 5. pp. 955-966.e4.

Bibtex

@article{58451fb7dc7241029fcb8afa45103611,
title = "Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91",
abstract = "SUCNR1 is an auto- and paracrine sensor of the metabolic stress signal succinate. Using unsupervised molecular dynamics (MD) simulations (170.400 ns) and mutagenesis across human, mouse, and rat SUCNR1, we characterize how a five-arginine motif around the extracellular pole of TM-VI determines the initial capture of succinate in the extracellular vestibule (ECV) to either stay or move down to the orthosteric site. Metadynamics demonstrate low-energy succinate binding in both sites, with an energy barrier corresponding to an intermediate stage during which succinate, with an associated water cluster, unlocks the hydrogen-bond-stabilized conformationally constrained extracellular loop (ECL)-2b. Importantly, simultaneous binding of two succinate molecules through either a {"}sequential{"} or {"}bypassing{"} mode is a frequent endpoint. The mono-carboxylate NF-56-EJ40 antagonist enters SUCNR1 between TM-I and -II and does not unlock ECL-2b. It is proposed that occupancy of both high-affinity sites is required for selective activation of SUCNR1 by high local succinate concentrations.",
author = "Aslihan Shenol and Michael L{\"u}ckmann and Mette Trauelsen and Matteo Lambrughi and Matteo Tiberti and Elena Papaleo and Frimurer, {Thomas M} and Schwartz, {Thue W}",
note = "Copyright {\textcopyright} 2024 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2024",
doi = "10.1016/j.molcel.2024.01.011",
language = "English",
volume = "84",
pages = "955--966.e4",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",

}

RIS

TY - JOUR

T1 - Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91

AU - Shenol, Aslihan

AU - Lückmann, Michael

AU - Trauelsen, Mette

AU - Lambrughi, Matteo

AU - Tiberti, Matteo

AU - Papaleo, Elena

AU - Frimurer, Thomas M

AU - Schwartz, Thue W

N1 - Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2024

Y1 - 2024

N2 - SUCNR1 is an auto- and paracrine sensor of the metabolic stress signal succinate. Using unsupervised molecular dynamics (MD) simulations (170.400 ns) and mutagenesis across human, mouse, and rat SUCNR1, we characterize how a five-arginine motif around the extracellular pole of TM-VI determines the initial capture of succinate in the extracellular vestibule (ECV) to either stay or move down to the orthosteric site. Metadynamics demonstrate low-energy succinate binding in both sites, with an energy barrier corresponding to an intermediate stage during which succinate, with an associated water cluster, unlocks the hydrogen-bond-stabilized conformationally constrained extracellular loop (ECL)-2b. Importantly, simultaneous binding of two succinate molecules through either a "sequential" or "bypassing" mode is a frequent endpoint. The mono-carboxylate NF-56-EJ40 antagonist enters SUCNR1 between TM-I and -II and does not unlock ECL-2b. It is proposed that occupancy of both high-affinity sites is required for selective activation of SUCNR1 by high local succinate concentrations.

AB - SUCNR1 is an auto- and paracrine sensor of the metabolic stress signal succinate. Using unsupervised molecular dynamics (MD) simulations (170.400 ns) and mutagenesis across human, mouse, and rat SUCNR1, we characterize how a five-arginine motif around the extracellular pole of TM-VI determines the initial capture of succinate in the extracellular vestibule (ECV) to either stay or move down to the orthosteric site. Metadynamics demonstrate low-energy succinate binding in both sites, with an energy barrier corresponding to an intermediate stage during which succinate, with an associated water cluster, unlocks the hydrogen-bond-stabilized conformationally constrained extracellular loop (ECL)-2b. Importantly, simultaneous binding of two succinate molecules through either a "sequential" or "bypassing" mode is a frequent endpoint. The mono-carboxylate NF-56-EJ40 antagonist enters SUCNR1 between TM-I and -II and does not unlock ECL-2b. It is proposed that occupancy of both high-affinity sites is required for selective activation of SUCNR1 by high local succinate concentrations.

U2 - 10.1016/j.molcel.2024.01.011

DO - 10.1016/j.molcel.2024.01.011

M3 - Journal article

C2 - 38325379

VL - 84

SP - 955-966.e4

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 5

ER -

ID: 382262476