{"id":"https://openalex.org/W7204887086","doi":"https://doi.org/10.64898/2026.08.31.748281","title":"Molecular basis of AMPA receptor labeling by ligand-directed acyl imidazole chemistry in living neurons","display_name":"Molecular basis of AMPA receptor labeling by ligand-directed acyl imidazole chemistry in living neurons","publication_year":2026,"publication_date":"2026-09-01","ids":{"openalex":"https://openalex.org/W7204887086","doi":"https://doi.org/10.64898/2026.08.31.748281"},"language":"en","primary_location":{"id":"doi:10.64898/2026.08.31.748281","doi":"https://doi.org/10.64898/2026.08.31.748281","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.08.31.748281","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/01/2026.08.31.748281.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc-nd","license_id":"https://openalex.org/licenses/cc-by-nc-nd","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"volume":null,"type":"preprint","is_traditional":true,"indexed_in":["crossref"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/01/2026.08.31.748281.full.pdf","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5044394093","display_name":"Dulce C. Guzm\u00e1n\u2010Ocampo","orcid":"https://orcid.org/0000-0001-6877-7025","observed_orcids":["https://orcid.org/0000-0001-6877-7025"]},"institutions":[{"id":"https://openalex.org/I169108374","display_name":"University of the Basque Country","ror":"https://ror.org/000xsnr85","country_code":"ES","type":"education","lineage":["https://openalex.org/I169108374"]},{"id":"https://openalex.org/I47686490","display_name":"Donostia International Physics Center","ror":"https://ror.org/02e24yw40","country_code":"ES","type":"other","lineage":["https://openalex.org/I47686490"]}],"countries":["ES"],"is_corresponding":false,"raw_author_name":"Dulce C. Guzm\u00e1n-Ocampo","raw_affiliation_strings":["Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, UPV/EHU & Donostia International Physics Center (DIPC), PK 1072, 20018 Donostia-San Sebastian, Euskadi, Spain"],"raw_orcid":"https://orcid.org/0000-0001-6877-7025","affiliations":[{"raw_affiliation_string":"Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, UPV/EHU & Donostia International Physics Center (DIPC), PK 1072, 20018 Donostia-San Sebastian, Euskadi, Spain","institution_ids":["https://openalex.org/I169108374","https://openalex.org/I47686490"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5054817549","display_name":"David De Sancho","orcid":"https://orcid.org/0000-0002-8985-2685","observed_orcids":["https://orcid.org/0000-0002-8985-2685"]},"institutions":[{"id":"https://openalex.org/I169108374","display_name":"University of the Basque Country","ror":"https://ror.org/000xsnr85","country_code":"ES","type":"education","lineage":["https://openalex.org/I169108374"]},{"id":"https://openalex.org/I47686490","display_name":"Donostia International Physics Center","ror":"https://ror.org/02e24yw40","country_code":"ES","type":"other","lineage":["https://openalex.org/I47686490"]}],"countries":["ES"],"is_corresponding":true,"raw_author_name":"David De Sancho","raw_affiliation_strings":["Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, UPV/EHU & Donostia International Physics Center (DIPC), PK 1072, 20018 Donostia-San Sebastian, Euskadi, Spain"],"raw_orcid":"https://orcid.org/0000-0002-8985-2685","affiliations":[{"raw_affiliation_string":"Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, UPV/EHU & Donostia International Physics Center (DIPC), PK 1072, 20018 Donostia-San Sebastian, Euskadi, Spain","institution_ids":["https://openalex.org/I169108374","https://openalex.org/I47686490"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5038379755","display_name":"Xabier L\u00f3pez","orcid":"https://orcid.org/0000-0002-2711-3588","observed_orcids":["https://orcid.org/0000-0002-2711-3588"]},"institutions":[{"id":"https://openalex.org/I169108374","display_name":"University of the Basque Country","ror":"https://ror.org/000xsnr85","country_code":"ES","type":"education","lineage":["https://openalex.org/I169108374"]},{"id":"https://openalex.org/I47686490","display_name":"Donostia International Physics Center","ror":"https://ror.org/02e24yw40","country_code":"ES","type":"other","lineage":["https://openalex.org/I47686490"]}],"countries":["ES"],"is_corresponding":false,"raw_author_name":"Xabier L\u00f3pez","raw_affiliation_strings":["Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, UPV/EHU & Donostia International Physics Center (DIPC), PK 1072, 20018 Donostia-San Sebastian, Euskadi, Spain"],"raw_orcid":"https://orcid.org/0000-0002-2711-3588","affiliations":[{"raw_affiliation_string":"Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, UPV/EHU & Donostia International Physics Center (DIPC), PK 1072, 20018 Donostia-San Sebastian, Euskadi, Spain","institution_ids":["https://openalex.org/I169108374","https://openalex.org/I47686490"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":2,"corresponding_author_ids":["https://openalex.org/A5054817549"],"corresponding_institution_ids":["https://openalex.org/I169108374","https://openalex.org/I47686490"],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":true,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T11440","display_name":"Click Chemistry and Applications","score":0.61080002784729,"subfield":{"id":"https://openalex.org/subfields/1605","display_name":"Organic Chemistry"},"field":{"id":"https://openalex.org/fields/16","display_name":"Chemistry"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}},"topics":[{"id":"https://openalex.org/T11440","display_name":"Click Chemistry and Applications","score":0.61080002784729,"subfield":{"id":"https://openalex.org/subfields/1605","display_name":"Organic Chemistry"},"field":{"id":"https://openalex.org/fields/16","display_name":"Chemistry"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}},{"id":"https://openalex.org/T10077","display_name":"Neuroscience and Neuropharmacology Research","score":0.1185000017285347,"subfield":{"id":"https://openalex.org/subfields/2804","display_name":"Cellular and Molecular Neuroscience"},"field":{"id":"https://openalex.org/fields/28","display_name":"Neuroscience"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10540","display_name":"Advanced Fluorescence Microscopy Techniques","score":0.03460000082850456,"subfield":{"id":"https://openalex.org/subfields/1304","display_name":"Biophysics"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/ampa-receptors","display_name":"AMPA receptors","score":0.8730000257492065},{"id":"https://openalex.org/keywords/covalent-protein-labeling","display_name":"covalent protein labeling","score":0.8859999775886536},{"id":"https://openalex.org/keywords/glua2","display_name":"GluA2","score":0.8730000257492065},{"id":"https://openalex.org/keywords/reaction-mechanism","display_name":"reaction mechanism","score":0.7570000290870667},{"id":"https://openalex.org/keywords/lysine-labeling","display_name":"lysine labeling","score":0.7400000095367432},{"id":"https://openalex.org/keywords/protein-microenvironment","display_name":"protein microenvironment","score":0.7979999780654907},{"id":"https://openalex.org/keywords/hydrogen-bond-network","display_name":"hydrogen bond network","score":0.6880000233650208},{"id":"https://openalex.org/keywords/ligand-binding-domain","display_name":"ligand-binding domain","score":0.9210000038146973},{"id":"https://openalex.org/keywords/quantum-chemical-calculations","display_name":"quantum chemical calculations","score":0.5720000267028809},{"id":"https://openalex.org/keywords/molecular-dynamics-simulation","display_name":"molecular dynamics simulation","score":0.8500000238418579},{"id":"https://openalex.org/keywords/reagent-design","display_name":"reagent design","score":0.5239999890327454}],"concepts":[{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.8659999966621399},{"id":"https://openalex.org/C40875361","wikidata":"https://www.wikidata.org/wiki/Q2356542","display_name":"Reagent","level":2,"score":0.7304999828338623},{"id":"https://openalex.org/C160268369","wikidata":"https://www.wikidata.org/wiki/Q295251","display_name":"AMPA receptor","level":4,"score":0.6215000152587891},{"id":"https://openalex.org/C178907741","wikidata":"https://www.wikidata.org/wiki/Q745930","display_name":"Nucleophile","level":3,"score":0.5971999764442444},{"id":"https://openalex.org/C30095370","wikidata":"https://www.wikidata.org/wiki/Q899488","display_name":"Protonation","level":3,"score":0.5047000050544739},{"id":"https://openalex.org/C116569031","wikidata":"https://www.wikidata.org/wiki/Q899107","display_name":"Ligand (biochemistry)","level":3,"score":0.49079999327659607},{"id":"https://openalex.org/C2780874372","wikidata":"https://www.wikidata.org/wiki/Q328692","display_name":"Imidazole","level":2,"score":0.4797999858856201},{"id":"https://openalex.org/C59593255","wikidata":"https://www.wikidata.org/wiki/Q901663","display_name":"Molecular dynamics","level":2,"score":0.44909998774528503},{"id":"https://openalex.org/C21951064","wikidata":"https://www.wikidata.org/wiki/Q899212","display_name":"Combinatorial chemistry","level":1,"score":0.43149998784065247},{"id":"https://openalex.org/C71240020","wikidata":"https://www.wikidata.org/wiki/Q186011","display_name":"Stereochemistry","level":1,"score":0.4106000065803528},{"id":"https://openalex.org/C112887158","wikidata":"https://www.wikidata.org/wiki/Q169324","display_name":"Hydrogen bond","level":3,"score":0.398499995470047},{"id":"https://openalex.org/C180577832","wikidata":"https://www.wikidata.org/wiki/Q127920","display_name":"Covalent bond","level":2,"score":0.3885999917984009},{"id":"https://openalex.org/C12554922","wikidata":"https://www.wikidata.org/wiki/Q7100","display_name":"Biophysics","level":1,"score":0.38690000772476196},{"id":"https://openalex.org/C171852809","wikidata":"https://www.wikidata.org/wiki/Q731154","display_name":"Chemical biology","level":2,"score":0.38019999861717224},{"id":"https://openalex.org/C53105671","wikidata":"https://www.wikidata.org/wiki/Q14777816","display_name":"Rational design","level":2,"score":0.3774999976158142},{"id":"https://openalex.org/C107824862","wikidata":"https://www.wikidata.org/wiki/Q616005","display_name":"Binding site","level":2,"score":0.3531999886035919},{"id":"https://openalex.org/C47701112","wikidata":"https://www.wikidata.org/wiki/Q735188","display_name":"Protein structure","level":2,"score":0.31859999895095825},{"id":"https://openalex.org/C65024703","wikidata":"https://www.wikidata.org/wiki/Q373406","display_name":"Reaction mechanism","level":3,"score":0.31690001487731934},{"id":"https://openalex.org/C178910836","wikidata":"https://www.wikidata.org/wiki/Q2196961","display_name":"Molecular model","level":2,"score":0.30320000648498535},{"id":"https://openalex.org/C179303850","wikidata":"https://www.wikidata.org/wiki/Q4300362","display_name":"Molecular recognition","level":3,"score":0.30250000953674316},{"id":"https://openalex.org/C147597530","wikidata":"https://www.wikidata.org/wiki/Q369472","display_name":"Computational chemistry","level":1,"score":0.2971000075340271},{"id":"https://openalex.org/C32123652","wikidata":"https://www.wikidata.org/wiki/Q2451605","display_name":"Molecular switch","level":3,"score":0.2897999882698059},{"id":"https://openalex.org/C41183919","wikidata":"https://www.wikidata.org/wiki/Q423026","display_name":"Active site","level":3,"score":0.28690001368522644},{"id":"https://openalex.org/C105768512","wikidata":"https://www.wikidata.org/wiki/Q7458208","display_name":"Reaction intermediate","level":3,"score":0.2854999899864197},{"id":"https://openalex.org/C11804247","wikidata":"https://www.wikidata.org/wiki/Q896177","display_name":"Protein\u2013protein interaction","level":2,"score":0.2696000039577484},{"id":"https://openalex.org/C41685203","wikidata":"https://www.wikidata.org/wiki/Q1974042","display_name":"Docking (animal)","level":2,"score":0.26649999618530273},{"id":"https://openalex.org/C177801218","wikidata":"https://www.wikidata.org/wiki/Q36534","display_name":"Chemical reaction","level":2,"score":0.2581999897956848},{"id":"https://openalex.org/C191120209","wikidata":"https://www.wikidata.org/wiki/Q908902","display_name":"Structural biology","level":2,"score":0.2531000077724457}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.64898/2026.08.31.748281","doi":"https://doi.org/10.64898/2026.08.31.748281","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.08.31.748281","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/01/2026.08.31.748281.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc-nd","license_id":"https://openalex.org/licenses/cc-by-nc-nd","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"}],"best_oa_location":{"id":"doi:10.64898/2026.08.31.748281","doi":"https://doi.org/10.64898/2026.08.31.748281","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.08.31.748281","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/01/2026.08.31.748281.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc-nd","license_id":"https://openalex.org/licenses/cc-by-nc-nd","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"sustainable_development_goals":[],"study_designs":[],"awards":[{"id":"https://openalex.org/G1401168639","display_name":null,"funder_award_id":"MICIU/AEI/10","funder_id":"https://openalex.org/F4320322930","funder_display_name":"Ministerio de Ciencia e Innovaci\u00f3n"},{"id":"https://openalex.org/G2309174360","display_name":null,"funder_award_id":"10.13039","funder_id":"https://openalex.org/F4320322930","funder_display_name":"Ministerio de Ciencia e Innovaci\u00f3n"},{"id":"https://openalex.org/G2339286796","display_name":null,"funder_award_id":"PID2024-158678NB-I00","funder_id":"https://openalex.org/F4320335598","funder_display_name":"Agencia Estatal de Investigaci\u00f3n"},{"id":"https://openalex.org/G2660406951","display_name":null,"funder_award_id":"/ AEI/10","funder_id":"https://openalex.org/F4320322930","funder_display_name":"Ministerio de Ciencia e Innovaci\u00f3n"},{"id":"https://openalex.org/G3480869486","display_name":null,"funder_award_id":"13039","funder_id":"https://openalex.org/F4320335598","funder_display_name":"Agencia Estatal de Investigaci\u00f3n"},{"id":"https://openalex.org/G3518538256","display_name":null,"funder_award_id":"13039","funder_id":"https://openalex.org/F4320322930","funder_display_name":"Ministerio de Ciencia e Innovaci\u00f3n"},{"id":"https://openalex.org/G5080475149","display_name":null,"funder_award_id":"10.13039","funder_id":"https://openalex.org/F4320335598","funder_display_name":"Agencia Estatal de Investigaci\u00f3n"},{"id":"https://openalex.org/G6033112984","display_name":null,"funder_award_id":"MICIU/AEI/10","funder_id":"https://openalex.org/F4320335322","funder_display_name":"European Regional Development Fund"},{"id":"https://openalex.org/G7084143925","display_name":null,"funder_award_id":"AEI/10","funder_id":"https://openalex.org/F4320335598","funder_display_name":"Agencia Estatal de Investigaci\u00f3n"},{"id":"https://openalex.org/G7123709766","display_name":null,"funder_award_id":"IT2067-26","funder_id":"https://openalex.org/F4320321705","funder_display_name":"Eusko Jaurlaritza"},{"id":"https://openalex.org/G8575141037","display_name":null,"funder_award_id":"MICIU/AEI/10.13039","funder_id":"https://openalex.org/F4320322930","funder_display_name":"Ministerio de Ciencia e Innovaci\u00f3n"}],"funders":[{"id":"https://openalex.org/F4320321705","display_name":"Eusko Jaurlaritza","ror":"https://ror.org/00pz2fp31"},{"id":"https://openalex.org/F4320322930","display_name":"Ministerio de Ciencia e Innovaci\u00f3n","ror":null},{"id":"https://openalex.org/F4320335322","display_name":"European Regional Development Fund","ror":"https://ror.org/00k4n6c32"},{"id":"https://openalex.org/F4320335598","display_name":"Agencia Estatal de Investigaci\u00f3n","ror":"https://ror.org/003x0zc53"}],"has_content":{"pdf":true,"grobid_xml":true},"content_urls":{"pdf":"https://content.openalex.org/works/W7204887086.pdf","grobid_xml":"https://content.openalex.org/works/W7204887086.grobid-xml"},"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W4393030226","https://openalex.org/W7204820541","https://openalex.org/W4285242316","https://openalex.org/W3162463337","https://openalex.org/W2102979750","https://openalex.org/W2111992556","https://openalex.org/W2746097926","https://openalex.org/W2746704583","https://openalex.org/W2275509795","https://openalex.org/W3126504866"],"abstract_inverted_index":{"Abstract":[0],"Rational":[1],"design":[2,239,254],"of":[3,15,68,174,255],"covalent":[4],"protein-labeling":[5],"reagents":[6,58,105],"in":[7,62,128],"complex":[8],"biological":[9],"environments":[10],"requires":[11],"a":[12,49,96,223],"molecular-level":[13],"understanding":[14],"how":[16,109],"the":[17,63,65,72,75,110,160,171,175,205,209,217,227,243,252],"protein":[18,52,73,111],"microenvironment":[19,112],"governs":[20,113],"chemical":[21,211],"reactivity;":[22],"yet,":[23],"such":[24],"mechanistic":[25],"details":[26,67],"remain":[27,78],"inaccessible":[28],"to":[29,44,94,107,159,200],"experimental":[30],"methods":[31],"alone.":[32],"In":[33,80],"living":[34],"neurons,":[35],"Ligand-Directed":[36],"Acyl":[37],"Imidazole":[38],"(LDAI)":[39],"chemistry":[40],"has":[41],"been":[42,60],"used":[43],"label":[45],"AMPA":[46],"receptors":[47],"as":[48,163],"traceless,":[50],"affinity-based":[51],"labeling":[53,57,102,136,186],"method.":[54],"Although":[55,115],"LDAI":[56,104,154,206,256],"have":[59],"optimized":[61],"lab,":[64],"atomic":[66],"their":[69],"interactions":[70,215],"with":[71,144,216],"and":[74,89,106,124,192,203,246],"underlying":[76],"mechanism":[77,99],"elusive.":[79],"this":[81],"work,":[82],"we":[83],"combined":[84],"Quantum":[85],"Mechanical":[86],"(QM)":[87],"calculations":[88],"molecular":[90],"dynamics":[91],"(MD)":[92],"simulations":[93,149],"propose":[95],"detailed":[97],"reaction":[98],"for":[100,226,241,251],"AMPAR":[101,162],"by":[103],"clarify":[108],"reactivity.":[114],"Lys":[116,135],"residues":[117],"are":[118],"usually":[119],"protonated":[120],"at":[121],"physiological":[122],"pH":[123],"therefore":[125],"less":[126],"nucleophilic":[127],"water,":[129],"our":[130,236],"QM":[131],"results":[132,237],"show":[133],"that":[134,151,169,181,197],"is":[137],"energetically":[138],"more":[139],"favorable":[140],"than":[141],"competing":[142],"reactions":[143],"Ser":[145],"or":[146],"water.":[147],"MD":[148],"reveal":[150],"PFQX":[152],"\u2014the":[153],"reagent":[155,244],"precursor\u2014":[156],"binds":[157],"dynamically":[158],"GluA2":[161],"an":[164],"antagonist,":[165],"inducing":[166],"conformational":[167],"changes":[168],"reshape":[170],"local":[172],"environment":[173],"acyl":[176],"imidazole":[177],"(AI)":[178],"warhead,":[179],"underscoring":[180],"ligand":[182],"identity":[183],"strongly":[184],"affects":[185],"outcomes.":[187],"We":[188],"also":[189],"identified":[190],"intra":[191],"intermolecular":[193],"hydrogen":[194],"bond":[195],"networks":[196,250],"may":[198],"contribute":[199],"further":[201],"immobilize":[202],"pre-organize":[204],"reagent.":[207],"Moreover,":[208],"probe\u2019s":[210],"nature":[212],"shapes":[213],"its":[214],"Ligand":[218],"Binding":[219],"Domain":[220],"(LBD),":[221],"offering":[222],"plausible":[224],"rationale":[225],"previously":[228],"experimentally":[229],"observed":[230],"ligand-dependent":[231],"fluorescent":[232],"response.":[233],"Taken":[234],"together,":[235],"establish":[238],"principles":[240],"exploiting":[242],"geometry":[245],"binding":[247],"pocket":[248],"hydrogen-bonding":[249],"rational":[253],"reagents.":[257]},"counts_by_year":[],"updated_date":"2026-11-09T13:22:03.289127","created_date":"2026-09-02T00:00:00"}
