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dc.contributor.authorBenito-Muñoz, Cristina
dc.contributor.authorPerona, Almudena
dc.contributor.authorFelipe, Raquel
dc.contributor.authorPérez-Siles, Gonzalo
dc.contributor.authorNúñez, Enrique
dc.contributor.authorAragón, Carmen
dc.contributor.authorLópez Corcuera, Beatriz 
dc.contributor.otherUAM. Departamento de Biología Moleculares_ES
dc.date.accessioned2022-03-07T08:49:32Z
dc.date.available2022-03-07T08:49:32Z
dc.date.issued2021-05-18
dc.identifier.citationACS Chemical Neuroscience 12.11 (2021): 1860-1872en_US
dc.identifier.issn1383-5866 (print)es_ES
dc.identifier.urihttp://hdl.handle.net/10486/700581
dc.description.abstractThe neuronal glycine transporter GlyT2 modulates inhibitory glycinergic neurotransmission by controlling the extracellular concentration of synaptic glycine and the supply of neurotransmitter to the presynaptic terminal. Spinal cord glycinergic neurons present in the dorsal horn diminish their activity in pathological pain conditions and behave as gate keepers of the touch-pain circuitry. The pharmacological blockade of GlyT2 reduces the progression of the painful signal to rostral areas of the central nervous system by increasing glycine extracellular levels, so it has analgesic action. O-[(2-benzyloxyphenyl-3-fluorophenyl)methyl]-L-serine (ALX1393) and N-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-(phenylmethoxy)benzamide (ORG25543) are two selective GlyT2 inhibitors with nanomolar affinity for the transporter and analgesic effects in pain animal models, although with deficiencies which preclude further clinical development. In this report, we performed a comparative ligand docking of ALX1393 and ORG25543 on a validated GlyT2 structural model including all ligand sites constructed by homology with the crystallized dopamine transporter from Drosophila melanogaster. Molecular dynamics simulations and energy analysis of the complex and functional analysis of a series of point mutants permitted to determine the structural determinants of ALX1393 and ORG25543 discrimination by GlyT2. The ligands establish simultaneous contacts with residues present in transmembrane domains 1, 3, 6, and 8 and block the transporter in outward-facing conformation and hence inhibit glycine transport. In addition, differential interactions of ALX1393 with the cation bound at Na1 site and ORG25543 with TM10 define the differential sites of the inhibitors and explain some of their individual features. Structural information about the interactions with GlyT2 may provide useful tools for new drug discoveryen_US
dc.description.sponsorshipThis work was supported by grants of the Spanish ‘Ministerio de Economía y Competitividad’, grant number SAF2017-84235-R (AEI/FEDER, EU) to B.L.-C. and by institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSOen_US
dc.format.extent13 pag.es_ES
dc.format.mimetypeapplication/pdfes_ES
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofACS Chemical Neuroscienceen_US
dc.rights© 2021 American Chemical Societyen_US
dc.subject.otherALX1393en_US
dc.subject.otherORG25543en_US
dc.subject.otherGlycinergic neurotransmissionen_US
dc.subject.otherInhibitor bindingen_US
dc.subject.otherNeuronal glycine transporter 2en_US
dc.subject.otherPainen_US
dc.titleStructural determinants of the neuronal glycine transporter 2 for the selective inhibitors ALX1393 and ORG25543en_US
dc.typearticleen_US
dc.subject.ecienciaBiología y Biomedicina / Biologíaes_ES
dc.relation.publisherversionhttps://doi.org/10.1021/acschemneuro.0c00602es_ES
dc.identifier.doi10.1021/acschemneuro.0c00602es_ES
dc.identifier.publicationfirstpage1860es_ES
dc.identifier.publicationissue11es_ES
dc.identifier.publicationlastpage1872es_ES
dc.identifier.publicationvolume12es_ES
dc.relation.projectIDGobierno de España. SAF2017-84235-Res_ES
dc.type.versioninfo:eu-repo/semantics/publishedVersiones_ES
dc.rights.ccReconocimientoes_ES
dc.rights.accessRightsopenAccessen_US
dc.authorUAMBenito Muñoz, Cristina (271715)
dc.authorUAMLópez Corcuera, Beatriz (260282)
dc.authorUAMAragón Rueda, Carmen (258951)
dc.facultadUAMFacultad de Cienciases_ES
dc.institutoUAMInstituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)es_ES
dc.institutoUAMCentro de Biología Molecular Severo Ochoa (CBMSO)es_ES


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