Mechanistic Studies on the Stereoselectivity of the Serotonin 5-HT1A Receptor

Overview

Journal Angew Chem Int Ed Engl

Specialty Chemistry

Date 2016 Jun 1

PMID 27244650

Citations 12

Authors

Shuguang Yuan

Qian Peng

Krzysztof Palczewski

Horst Vogel

Slawomir Filipek

Affiliations

Soon will be listed here.

Abstract

G-protein-coupled receptors (GPCRs) are involved in a wide range of physiological processes, and they have attracted considerable attention as important targets for developing new medicines. A central and largely unresolved question in drug discovery, which is especially relevant to GPCRs, concerns ligand selectivity: Why do certain molecules act as activators (agonists) whereas others, with nearly identical structures, act as blockers (antagonists) of GPCRs? To address this question, we employed all-atom, long-timescale molecular dynamics simulations to investigate how two diastereomers (epimers) of dihydrofuroaporphine bind to the serotonin 5-HT1A receptor and exert opposite effects. By using molecular interaction fingerprints, we discovered that the agonist could mobilize nearby amino acid residues to act as molecular switches for the formation of a continuous water channel. In contrast, the antagonist epimer remained firmly stabilized in the binding pocket.

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References

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

Yuan S, Hu Z, Filipek S, Vogel H . W246(6.48) opens a gate for a continuous intrinsic water pathway during activation of the adenosine A2A receptor. Angew Chem Int Ed Engl. 2014; 54(2):556-9. DOI: 10.1002/anie.201409679. View

Yuan S, Ghoshdastider U, Trzaskowski B, Latek D, Debinski A, Pulawski W . The role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations. PLoS One. 2012; 7(11):e47114. PMC: 3506623. DOI: 10.1371/journal.pone.0047114. View

Lu H . Stereoselectivity in drug metabolism. Expert Opin Drug Metab Toxicol. 2007; 3(2):149-58. DOI: 10.1517/17425255.3.2.149. View

Gorinski N, Kowalsman N, Renner U, Wirth A, Reinartz M, Seifert R . Computational and experimental analysis of the transmembrane domain 4/5 dimerization interface of the serotonin 5-HT(1A) receptor. Mol Pharmacol. 2012; 82(3):448-63. DOI: 10.1124/mol.112.079137. View

Yuan S, Wu R, Latek D, Trzaskowski B, Filipek S . Lipid receptor S1P₁ activation scheme concluded from microsecond all-atom molecular dynamics simulations. PLoS Comput Biol. 2013; 9(10):e1003261. PMC: 3789783. DOI: 10.1371/journal.pcbi.1003261. View

Mehvar R, Brocks D, Vakily M . Impact of stereoselectivity on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs. Clin Pharmacokinet. 2002; 41(8):533-58. DOI: 10.2165/00003088-200241080-00001. View

Wacker D, Wang C, Katritch V, Han G, Huang X, Vardy E . Structural features for functional selectivity at serotonin receptors. Science. 2013; 340(6132):615-9. PMC: 3644390. DOI: 10.1126/science.1232808. View

Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S . Action of molecular switches in GPCRs--theoretical and experimental studies. Curr Med Chem. 2012; 19(8):1090-109. PMC: 3343417. DOI: 10.2174/092986712799320556. View

10.

Kruse A, Kobilka B, Gautam D, Sexton P, Christopoulos A, Wess J . Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov. 2014; 13(7):549-60. PMC: 5818261. DOI: 10.1038/nrd4295. View

11.

Wolf M, Hoefling M, Aponte-Santamaria C, Grubmuller H, Groenhof G . g_membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation. J Comput Chem. 2010; 31(11):2169-74. DOI: 10.1002/jcc.21507. View

12.

Lakkaraju S, Lemkul J, Huang J, MacKerell Jr A . DIRECT-ID: An automated method to identify and quantify conformational variations--application to β2 -adrenergic GPCR. J Comput Chem. 2015; 37(4):416-25. PMC: 4756637. DOI: 10.1002/jcc.24231. View

13.

Klauda J, Venable R, Freites J, OConnor J, Tobias D, Mondragon-Ramirez C . Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J Phys Chem B. 2010; 114(23):7830-43. PMC: 2922408. DOI: 10.1021/jp101759q. View

14.

Fenalti G, Giguere P, Katritch V, Huang X, Thompson A, Cherezov V . Molecular control of δ-opioid receptor signalling. Nature. 2014; 506(7487):191-6. PMC: 3931418. DOI: 10.1038/nature12944. View

15.

Rose A, Elgeti M, Zachariae U, Grubmuller H, Hofmann K, Scheerer P . Position of transmembrane helix 6 determines receptor G protein coupling specificity. J Am Chem Soc. 2014; 136(32):11244-7. DOI: 10.1021/ja5055109. View

16.

Yuan S, Vogel H, Filipek S . The role of water and sodium ions in the activation of the μ-opioid receptor. Angew Chem Int Ed Engl. 2013; 52(38):10112-5. DOI: 10.1002/anie.201302244. View

17.

Lomize A, Pogozheva I, Mosberg H . Anisotropic solvent model of the lipid bilayer. 2. Energetics of insertion of small molecules, peptides, and proteins in membranes. J Chem Inf Model. 2011; 51(4):930-46. PMC: 3091260. DOI: 10.1021/ci200020k. View

18.

Yuan S, Palczewski K, Peng Q, Kolinski M, Vogel H, Filipek S . The mechanism of ligand-induced activation or inhibition of μ- and κ-opioid receptors. Angew Chem Int Ed Engl. 2015; 54(26):7560-3. DOI: 10.1002/anie.201501742. View

19.

Yuan S, Peng Q, Palczewski K, Vogel H, Filipek S . Mechanistic Studies on the Stereoselectivity of the Serotonin 5-HT1A Receptor. Angew Chem Int Ed Engl. 2016; 55(30):8661-5. PMC: 4957245. DOI: 10.1002/anie.201603766. View

20.

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