Molecular Dynamics Simulations of the Allosteric Modulation of the Adenosine A2A Receptor by a Mini-G Protein

Overview

Journal Sci Rep

Specialty Science

Date 2019 Apr 4

PMID 30940903

Citations 9

Authors

Pedro Renault

Maxime Louet

Jacky Marie

Gilles Labesse

Nicolas Floquet

Affiliations

Soon will be listed here.

Abstract

Through their coupling to G proteins, G Protein-Coupled Receptors (GPCRs) trigger cellular responses to various signals. Some recent experiments have interestingly demonstrated that the G protein can also act on the receptor by favoring a closed conformation of its orthosteric site, even in the absence of a bound agonist. In this work, we explored such an allosteric modulation by performing extensive molecular dynamics simulations on the adenosine A2 receptor (A2AR) coupled to the Mini-Gs protein. In the presence of the Mini-Gs, we confirmed a restriction of the receptor's agonist binding site that can be explained by a modulation of the intrinsic network of contacts of the receptor. Of interest, we observed similar effects with the C-terminal helix of the Mini-Gs, showing that the observed effect on the binding pocket results from direct local contacts with the bound protein partner that cause a rewiring of the whole receptor's interaction network.

Citing Articles

The PIWI-specific insertion module helps load longer piRNAs for translational activation essential for male fertility.

Wang X, Lin D, Yan Y, Wang A, Liao J, Meng Q Sci China Life Sci. 2023; 66(7):1459-1481.

PMID: 37335463 DOI: 10.1007/s11427-023-2390-5.

On the force field optimisation of [Formula: see text]-lactam cores using the force field Toolkit.

Wu Q, Huang T, Xia S, Otto F, Lee T, Huang H J Comput Aided Mol Des. 2022; 36(7):537-547.

PMID: 35819650 PMC: 9399072. DOI: 10.1007/s10822-022-00464-3.

Glycosylation is key for enhancing drug recognition into spike glycoprotein of SARS-CoV-2.

Ropon-Palacios G, Perez-Silva J, Rojas-Humpire R, Olivos-Ramirez G, Chenet-Zuta M, Cornejo-Villanueva V Comput Biol Chem. 2022; 98:107668.

PMID: 35339763 PMC: 8941845. DOI: 10.1016/j.compbiolchem.2022.107668.

Allosteric Modulation of Adenosine A Receptors as a New Therapeutic Avenue.

Korkutata M, Agrawal L, Lazarus M Int J Mol Sci. 2022; 23(4).

PMID: 35216213 PMC: 8880556. DOI: 10.3390/ijms23042101.

Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 M.

Jimenez-Avalos G, Vargas-Ruiz A, Delgado-Pease N, Olivos-Ramirez G, Sheen P, Fernandez-Diaz M Sci Rep. 2021; 11(1):15452.

PMID: 34326429 PMC: 8322093. DOI: 10.1038/s41598-021-94951-6.

References

Miao Y, McCammon J . Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor. Proc Natl Acad Sci U S A. 2018; 115(12):3036-3041. PMC: 5866610. DOI: 10.1073/pnas.1800756115. View

Liu W, Chun E, Thompson A, Chubukov P, Xu F, Katritch V . Structural basis for allosteric regulation of GPCRs by sodium ions. Science. 2012; 337(6091):232-6. PMC: 3399762. DOI: 10.1126/science.1219218. View

Kang Y, Kuybeda O, de Waal P, Mukherjee S, Van Eps N, Dutka P . Cryo-EM structure of human rhodopsin bound to an inhibitory G protein. Nature. 2018; 558(7711):553-558. PMC: 8054211. DOI: 10.1038/s41586-018-0215-y. View

Motlagh H, Wrabl J, Li J, Hilser V . The ensemble nature of allostery. Nature. 2014; 508(7496):331-9. PMC: 4224315. DOI: 10.1038/nature13001. View

Rasenick M, Watanabe M, Lazarevic M, Hatta S, Hamm H . Synthetic peptides as probes for G protein function. Carboxyl-terminal G alpha s peptides mimic Gs and evoke high affinity agonist binding to beta-adrenergic receptors. J Biol Chem. 1994; 269(34):21519-25. View

Cheng R, Segala E, Robertson N, Deflorian F, Dore A, Errey J . Structures of Human A and A Adenosine Receptors with Xanthines Reveal Determinants of Selectivity. Structure. 2017; 25(8):1275-1285.e4. DOI: 10.1016/j.str.2017.06.012. View

Louet M, Karakas E, Perret A, Perahia D, Martinez J, Floquet N . Conformational restriction of G-proteins Coupled Receptors (GPCRs) upon complexation to G-proteins: a putative activation mode of GPCRs?. FEBS Lett. 2013; 587(16):2656-61. DOI: 10.1016/j.febslet.2013.06.052. View

Saleh N, Saladino G, Gervasio F, Clark T . Investigating allosteric effects on the functional dynamics of β2-adrenergic ternary complexes with enhanced-sampling simulations. Chem Sci. 2018; 8(5):4019-4026. PMC: 6094175. DOI: 10.1039/c6sc04647a. View

Pan H, Lee J, Hilser V . Binding sites in Escherichia coli dihydrofolate reductase communicate by modulating the conformational ensemble. Proc Natl Acad Sci U S A. 2000; 97(22):12020-5. PMC: 17287. DOI: 10.1073/pnas.220240297. View

10.

Lee S, Nivedha A, Tate C, Vaidehi N . Dynamic Role of the G Protein in Stabilizing the Active State of the Adenosine A Receptor. Structure. 2019; 27(4):703-712.e3. PMC: 6531377. DOI: 10.1016/j.str.2018.12.007. View

11.

Ferruz N, Doerr S, Vanase-Frawley M, Zou Y, Chen X, Marr E . Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs. Sci Rep. 2018; 8(1):897. PMC: 5772633. DOI: 10.1038/s41598-018-19345-7. View

12.

Nygaard R, Zou Y, Dror R, Mildorf T, Arlow D, Manglik A . The dynamic process of β(2)-adrenergic receptor activation. Cell. 2013; 152(3):532-42. PMC: 3586676. DOI: 10.1016/j.cell.2013.01.008. View

13.

DeVree B, Mahoney J, Velez-Ruiz G, Rasmussen S, Kuszak A, Edwald E . Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature. 2016; 535(7610):182-6. PMC: 5702553. DOI: 10.1038/nature18324. View

14.

Xu F, Wu H, Katritch V, Han G, Jacobson K, Gao Z . Structure of an agonist-bound human A2A adenosine receptor. Science. 2011; 332(6027):322-7. PMC: 3086811. DOI: 10.1126/science.1202793. View

15.

Jo S, Kim T, Im W . Automated builder and database of protein/membrane complexes for molecular dynamics simulations. PLoS One. 2007; 2(9):e880. PMC: 1963319. DOI: 10.1371/journal.pone.0000880. View

16.

Brinda K, Vishveshwara S . A network representation of protein structures: implications for protein stability. Biophys J. 2005; 89(6):4159-70. PMC: 1366981. DOI: 10.1529/biophysj.105.064485. View

17.

Mary S, Damian M, Louet M, Floquet N, Fehrentz J, Marie J . Ligands and signaling proteins govern the conformational landscape explored by a G protein-coupled receptor. Proc Natl Acad Sci U S A. 2012; 109(21):8304-9. PMC: 3361445. DOI: 10.1073/pnas.1119881109. View

18.

De Lean A, Stadel J, Lefkowitz R . A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. J Biol Chem. 1980; 255(15):7108-17. View

19.

Sali A, Blundell T . Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993; 234(3):779-815. DOI: 10.1006/jmbi.1993.1626. View

20.

Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J . CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem. 2009; 31(4):671-90. PMC: 2888302. DOI: 10.1002/jcc.21367. View