Hinge region mediates signal transmission of luteinizing hormone and chorionic gonadotropin receptor

He, Xinheng; Duan, Jia; Ji, Yujie; Zhao, Lifen; Jiang, Hualiang; Jiang, Yi; Xu, Hui; Cheng, Xi

doi:10.1016/j.csbj.2022.11.039

Cited by 9 publications

(6 citation statements)

References 60 publications

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“…By aligning the sequence of the TM of the FSHR (Y362-F630) and the LHCGR (D360-T630), we calculated a RMSD of 6.1 Å; both structures were consistent with the active (bound to G-protein) state conformation. The largest difference between the FSHR and LHCGR was observed in the HR domain, which deserves further detailed analysis because of its role on triggering the activation process of these receptors [ 20 , 31 ]. In this study, we explored the motion of the LRR, HR, and TM domain in a conformation consistent with the active state.…”

Section: Resultsmentioning

confidence: 99%

“…Both receptors were analyzed in a comparative manner following the same computational protocols. The internal coordinates were defined for measuring distances among the LRR, HR and TM domains to detect the relative motion of the HR, which is recognized as a key region involved in the activation of all GPHRs [ 20 , 31 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…The α-helix (P272-N280) and the loop P10 (F350-Y359) of the HR conform a communication interface between the LRR and the TM domain. For example, the α-helix Q425-T435 of the EL1 and P10 exhibit interactions in the inactivating S277I and activating E254K mutations, suggesting that the positions K354 and K605 are important regulators of the activation or inhibition of this receptor [ 20 ]. On the other hand, the C304-C336 disulfide bond was not observed in the crystal LHCGR structure, in contrast to the C292-C338 bond in the FSHR ( Fig 1A ).…”

Section: Introductionmentioning

confidence: 99%

“…Both GPCRs were relaxed in similar conditions through a simulation box that included water molecules as solvent, a polyunsaturated phospholipid membrane, and monovalent ions for charge balance. A difference to highlight between both structures is the presence of the disulfide bond C292-C338 at the HR of the FSHR, which is not observed in the equivalent position (C304-C336) in the LHCGR [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Tracking conformational transitions of the gonadotropin hormone receptors in a bilayer of (SDPC) poly-unsaturated lipids from all-atom molecular dynamics simulations

Jardón-Valadez,

Ulloa-Aguirre

2024

PLoS Comput Biol

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Glycoprotein hormone receptors [thyrotropin (TSHR), luteinizing hormone/chorionic gonadotropin (LHCGR), and follicle stimulating hormone (FSHR) receptors] are rhodopsin-like G protein-coupled receptors. These receptors display common structural features including a prominent extracellular domain with leucine-rich repeats (LRR) stabilized by β-sheets and a long and flexible loop known as the hinge region (HR), and a transmembrane (TM) domain with seven α-helices interconnected by intra- and extracellular loops. Binding of the ligand to the LRR resembles a hand coupling transversally to the α- and β-subunits of the hormone, with the thumb being the HR. The structure of the FSH-FSHR complex suggests an activation mechanism in which Y335 at the HR binds into a pocket between the α- and β-chains of the hormone, leading to an adjustment of the extracellular loops. In this study, we performed molecular dynamics (MD) simulations to identify the conformational changes of the FSHR and LHCGR. We set up a FSHR structure as predicted by AlphaFold (AF-P23945); for the LHCGR structure we took the cryo-electron microscopy structure for the active state (PDB:7FII) as initial coordinates. Specifically, the flexibility of the HR domain and the correlated motions of the LRR and TM domain were analyzed. From the conformational changes of the LRR, TM domain, and HR we explored the conformational landscape by means of MD trajectories in all-atom approximation, including a membrane of polyunsaturated phospholipids. The distances and procedures here defined may be useful to propose reaction coordinates to describe diverse processes, such as the active-to-inactive transition, and to identify intermediaries suited for allosteric regulation and biased binding to cellular transducers in a selective activation strategy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tracking conformational transitions of the gonadotropin hormone receptors in a bilayer of (SDPC) poly-unsaturated lipids from all-atom molecular dynamics simulations

Jardón-Valadez,

Ulloa-Aguirre

2024

PLoS Comput Biol

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“…One notable observation from AI 2 BMD simulation is the increased flexibility in protein movements, which was also observed in MLFF's simulations 10 . The ability to accurately model the flexibility of proteins is crucial in understanding their functions [30][31][32] . By incorporating such details into protein simulations, AI 2 BMD can provide a more comprehensive and accurate picture of protein behavior 33 .…”

Section: Discussionmentioning

confidence: 99%

AI²BMD: efficient characterization of protein dynamics withab initioaccuracy

Wang

et al. 2023

Preprint

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Biomolecular dynamics simulation is a fundamental technology for life sciences research, and its usefulness depends on its accuracy and efficiency. Classical molecular dynamics simulation is fast but lacks chemical accuracy. Quantum chemistry methods like density functional theory (DFT) can reach chemical accuracy but cannot scale to support large biomolecules. We introduce an AI-based ab initio biomolecular dynamics system (AI2BMD) that can efficiently simulate large biomolecules with ab initio accuracy. AI2BMD uses a protein fragmentation scheme and machine learning force field to achieve generalizable ab initio accuracy for energy and force calculations for various proteins comprising over 10,000 atoms. Compared to DFT, it reduces computational time by several orders of magnitude. With several hundred nanoseconds of dynamics simulations, AI2BMD demonstrated its capability of efficiently exploring the conformational space of peptides and proteins, deriving accurate 3J-couplings that match NMR experiments, and showing protein folding and unfolding tendencies. Furthermore, AI2BMD enables precise free energy calculations for protein folding, and the estimated melting temperatures are well aligned with experiments. AI2BMD could potentially complement wet-lab experiments, detect the dynamic processes of bioactivities, and enable biomedical research that is currently impossible to conduct.

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Luteinizing hormone (LH)

Casarini,

Santi,

Marshall

et al. 2024

Reference Module in Biomedical Sciences

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Hinge region mediates signal transmission of luteinizing hormone and chorionic gonadotropin receptor

Cited by 9 publications

References 60 publications

Tracking conformational transitions of the gonadotropin hormone receptors in a bilayer of (SDPC) poly-unsaturated lipids from all-atom molecular dynamics simulations

Tracking conformational transitions of the gonadotropin hormone receptors in a bilayer of (SDPC) poly-unsaturated lipids from all-atom molecular dynamics simulations

AI²BMD: efficient characterization of protein dynamics withab initioaccuracy

Luteinizing hormone (LH)

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Hinge region mediates signal transmission of luteinizing hormone and chorionic gonadotropin receptor

Cited by 9 publications

References 60 publications

Tracking conformational transitions of the gonadotropin hormone receptors in a bilayer of (SDPC) poly-unsaturated lipids from all-atom molecular dynamics simulations

Tracking conformational transitions of the gonadotropin hormone receptors in a bilayer of (SDPC) poly-unsaturated lipids from all-atom molecular dynamics simulations

AI2BMD: efficient characterization of protein dynamics withab initioaccuracy

Luteinizing hormone (LH)

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AI²BMD: efficient characterization of protein dynamics withab initioaccuracy