The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol

(-)-Δ-trans-tetrahydrocannabinol (THC), which is the principal psychoactive constituent of Cannabis, mediates its action by binding to two members of the G-protein-coupled receptor (GPCR) family: the cannabinoid CB (CBR) and CB (CBR) receptors. Molecular dynamics simulations showed that the pentyl c...

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Autores: Llinas del Torrent, Claudia|||0000-0002-6772-6856, Raïch, Iu|||0000-0001-6271-0495, Gonzalez, Angel|||0000-0002-2284-8307, Casajuana-Martin, Nil|||0000-0002-9007-274X, Lillo, Jaume, Rebassa, Joan Biel, Ferreiro-Vera, Carlos, Sánchez de Medina, Verónica, Franco, Rafael|||0000-0003-2549-4919, Navarro Brugal, Gemma|||0000-0003-4654-0873, Pardo Carrasco, Leonardo|||0000-0003-1778-7420
Formato: artículo
Fecha de publicación:2023
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:307259
Acesso em linha:https://ddd.uab.cat/record/307259
https://dx.doi.org/urn:doi:10.1021/acs.jcim.3c01054
Access Level:acceso abierto
Palavra-chave:Alkyl chain
Binding modes
Cannabinoid receptors
Cannabinoids
Carbon chains
Dynamics simulation
G protein coupled receptors
Intracellular cavities
Receptor activation
Side-chains
Cannabinoid Receptor Agonists
Dronabinol
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Receptors, Cannabinoid
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oai_identifier_str oai:ddd.uab.cat:307259
network_acronym_str ES
network_name_str España
repository_id_str
spelling The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-TetrahydrocannabinolLlinas del Torrent, Claudia|||0000-0002-6772-6856Raïch, Iu|||0000-0001-6271-0495Gonzalez, Angel|||0000-0002-2284-8307Casajuana-Martin, Nil|||0000-0002-9007-274XLillo, JaumeRebassa, Joan BielFerreiro-Vera, CarlosSánchez de Medina, VerónicaFranco, Rafael|||0000-0003-2549-4919Navarro Brugal, Gemma|||0000-0003-4654-0873Pardo Carrasco, Leonardo|||0000-0003-1778-7420Alkyl chainBinding modesCannabinoid receptorsCannabinoidsCarbon chainsDynamics simulationG protein coupled receptorsIntracellular cavitiesReceptor activationSide-chainsCannabinoid Receptor AgonistsDronabinolReceptor, Cannabinoid, CB1Receptor, Cannabinoid, CB2Receptors, Cannabinoid(-)-Δ-trans-tetrahydrocannabinol (THC), which is the principal psychoactive constituent of Cannabis, mediates its action by binding to two members of the G-protein-coupled receptor (GPCR) family: the cannabinoid CB (CBR) and CB (CBR) receptors. Molecular dynamics simulations showed that the pentyl chain of THC could adopts an I-shape conformation, filling an intracellular cavity between Phe and Trp for initial agonist-induced receptor activation, in CBR but not in CBR. This cavity opens to the five-carbon chain of THC by the conformational change of the γ-branched, flexible, Leu side chain of CBR, which is not feasible by the β-branched, mode rigid, Val side chain of CBR. In agreement with our computational results, THC could not decrease the forskolin-induced cAMP levels in cells expressing mutant CBR receptor but could activate the mutant CBR receptor as efficiently as wild-type CBR. Additionally, JWH-133, a full CBR agonist, contains a branched dimethyl moiety in the ligand chain that bridges Phe and Val for receptor activation. In this case, the substitution of Val to Leu in CBR makes JWH-133 unable to activate CBR. In conclusion, our combined computational and experimental results have shown that the amino acid at position 6.51 is a key additional player in the initial mechanism of activation of GPCRs that recognize signaling molecules derived from lipid species. 22023-01-0120232023-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/307259https://dx.doi.org/urn:doi:10.1021/acs.jcim.3c01054reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 BES-2017-081872Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2021/SGR-00304Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PDC2022-133171-I00Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 ID2020-113430RB-I00Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 D2021-126600OB-I00Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2022-140912OB-I00open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3072592026-06-06T12:50:31Z
dc.title.none.fl_str_mv The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol
title The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol
spellingShingle The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol
Llinas del Torrent, Claudia|||0000-0002-6772-6856
Alkyl chain
Binding modes
Cannabinoid receptors
Cannabinoids
Carbon chains
Dynamics simulation
G protein coupled receptors
Intracellular cavities
Receptor activation
Side-chains
Cannabinoid Receptor Agonists
Dronabinol
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Receptors, Cannabinoid
title_short The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol
title_full The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol
title_fullStr The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol
title_full_unstemmed The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol
title_sort The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol
dc.creator.none.fl_str_mv Llinas del Torrent, Claudia|||0000-0002-6772-6856
Raïch, Iu|||0000-0001-6271-0495
Gonzalez, Angel|||0000-0002-2284-8307
Casajuana-Martin, Nil|||0000-0002-9007-274X
Lillo, Jaume
Rebassa, Joan Biel
Ferreiro-Vera, Carlos
Sánchez de Medina, Verónica
Franco, Rafael|||0000-0003-2549-4919
Navarro Brugal, Gemma|||0000-0003-4654-0873
Pardo Carrasco, Leonardo|||0000-0003-1778-7420
author Llinas del Torrent, Claudia|||0000-0002-6772-6856
author_facet Llinas del Torrent, Claudia|||0000-0002-6772-6856
Raïch, Iu|||0000-0001-6271-0495
Gonzalez, Angel|||0000-0002-2284-8307
Casajuana-Martin, Nil|||0000-0002-9007-274X
Lillo, Jaume
Rebassa, Joan Biel
Ferreiro-Vera, Carlos
Sánchez de Medina, Verónica
Franco, Rafael|||0000-0003-2549-4919
Navarro Brugal, Gemma|||0000-0003-4654-0873
Pardo Carrasco, Leonardo|||0000-0003-1778-7420
author_role author
author2 Raïch, Iu|||0000-0001-6271-0495
Gonzalez, Angel|||0000-0002-2284-8307
Casajuana-Martin, Nil|||0000-0002-9007-274X
Lillo, Jaume
Rebassa, Joan Biel
Ferreiro-Vera, Carlos
Sánchez de Medina, Verónica
Franco, Rafael|||0000-0003-2549-4919
Navarro Brugal, Gemma|||0000-0003-4654-0873
Pardo Carrasco, Leonardo|||0000-0003-1778-7420
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alkyl chain
Binding modes
Cannabinoid receptors
Cannabinoids
Carbon chains
Dynamics simulation
G protein coupled receptors
Intracellular cavities
Receptor activation
Side-chains
Cannabinoid Receptor Agonists
Dronabinol
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Receptors, Cannabinoid
topic Alkyl chain
Binding modes
Cannabinoid receptors
Cannabinoids
Carbon chains
Dynamics simulation
G protein coupled receptors
Intracellular cavities
Receptor activation
Side-chains
Cannabinoid Receptor Agonists
Dronabinol
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Receptors, Cannabinoid
description (-)-Δ-trans-tetrahydrocannabinol (THC), which is the principal psychoactive constituent of Cannabis, mediates its action by binding to two members of the G-protein-coupled receptor (GPCR) family: the cannabinoid CB (CBR) and CB (CBR) receptors. Molecular dynamics simulations showed that the pentyl chain of THC could adopts an I-shape conformation, filling an intracellular cavity between Phe and Trp for initial agonist-induced receptor activation, in CBR but not in CBR. This cavity opens to the five-carbon chain of THC by the conformational change of the γ-branched, flexible, Leu side chain of CBR, which is not feasible by the β-branched, mode rigid, Val side chain of CBR. In agreement with our computational results, THC could not decrease the forskolin-induced cAMP levels in cells expressing mutant CBR receptor but could activate the mutant CBR receptor as efficiently as wild-type CBR. Additionally, JWH-133, a full CBR agonist, contains a branched dimethyl moiety in the ligand chain that bridges Phe and Val for receptor activation. In this case, the substitution of Val to Leu in CBR makes JWH-133 unable to activate CBR. In conclusion, our combined computational and experimental results have shown that the amino acid at position 6.51 is a key additional player in the initial mechanism of activation of GPCRs that recognize signaling molecules derived from lipid species.
publishDate 2023
dc.date.none.fl_str_mv 2
2023-01-01
2023
2023-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/307259
https://dx.doi.org/urn:doi:10.1021/acs.jcim.3c01054
url https://ddd.uab.cat/record/307259
https://dx.doi.org/urn:doi:10.1021/acs.jcim.3c01054
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 BES-2017-081872
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2021/SGR-00304
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PDC2022-133171-I00
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 ID2020-113430RB-I00
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 D2021-126600OB-I00
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2022-140912OB-I00
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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