{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:12:38Z","timestamp":1791234758573,"version":"4.1.0"},"reference-count":138,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T00:00:00Z","timestamp":1674604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["PI 1672\/3-1"],"award-info":[{"award-number":["PI 1672\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>With approximately 400 encoding genes in humans, odorant receptors (ORs) are the largest subfamily of class A G protein-coupled receptors (GPCRs). Despite its high relevance and representation, the odorant-GPCRome is structurally poorly characterized: no experimental structures are available, and the low sequence identity of ORs to experimentally solved GPCRs is a significant challenge for their modeling. Moreover, the receptive range of most ORs is unknown. The odorant receptor OR5K1 was recently and comprehensively characterized in terms of cognate agonists. Here, we report two additional agonists and functional data of the most potent compound on two mutants, L1043.32 and L2556.51. Experimental data was used to guide the investigation of the binding modes of OR5K1 ligands into the orthosteric binding site using structural information from AI-driven modeling, as recently released in the AlphaFold Protein Structure Database, and from homology modeling. Induced-fit docking simulations were used to sample the binding site conformational space for ensemble docking. Mutagenesis data guided side chain residue sampling and model selection. We obtained models that could better rationalize the different activity of active (agonist) versus inactive molecules with respect to starting models and also capture differences in activity related to minor structural differences. Therefore, we provide a model refinement protocol that can be applied to model the orthosteric binding site of ORs as well as that of GPCRs with low sequence identity to available templates.<\/jats:p>","DOI":"10.1021\/acs.jcim.2c00752","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T19:47:18Z","timestamp":1674676038000},"page":"2014-2029","source":"Crossref","is-referenced-by-count":29,"title":["Modeling the Orthosteric Binding Site of the G Protein-Coupled\nOdorant Receptor OR5K1"],"prefix":"10.1021","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6177-9749","authenticated-orcid":true,"given":"Alessandro","family":"Nicoli","sequence":"first","affiliation":[{"name":"Leibniz Institute for Food Systems Biology at the Technical University of Munich , ,","place":["Freising, Germany, 85354"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4210-0475","authenticated-orcid":true,"given":"Franziska","family":"Haag","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Food Systems Biology at the Technical University of Munich , ,","place":["Freising, Germany, 85354"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Marcinek","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Food Systems Biology at the Technical University of Munich , ,","place":["Freising, Germany, 85354"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiming","family":"He","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Food Systems Biology at the Technical University of Munich , ,","place":["Freising, Germany, 85354"]},{"name":"Technical University of Munich , , ,","place":["Garching, Germany, 85748"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Krei\u00dfl","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Food Systems Biology at the Technical University of Munich , ,","place":["Freising, Germany, 85354"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u0308rg","family":"Stein","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Food Systems Biology at the Technical University of Munich , ,","place":["Freising, Germany, 85354"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Marchetto","sequence":"additional","affiliation":[{"name":"Forschungszentrum Ju\u0308lich , , ,","place":["Ju\u0308lich, Germany, 52428"]},{"name":"RWTH Aachen University , , ,","place":["Aachen, Germany, 52074"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4445-6144","authenticated-orcid":true,"given":"Andreas","family":"Dunkel","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Food Systems Biology at the Technical University of Munich , ,","place":["Freising, Germany, 85354"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4057-7165","authenticated-orcid":true,"given":"Thomas","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Technical University of Munich , , ,","place":["Freising, Germany, 85354"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3350-8682","authenticated-orcid":true,"given":"Dietmar","family":"Krautwurst","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Food Systems Biology at the Technical University of Munich , ,","place":["Freising, Germany, 85354"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8520-5165","authenticated-orcid":true,"given":"Antonella","family":"Di Pizio","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Food Systems Biology at the Technical University of Munich , ,","place":["Freising, Germany, 85354"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2023,1,25]]},"reference":[{"key":"2026081804441346200_cit1","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1083\/jcb.145.5.927","article-title":"Heptahelical\nreceptor signaling:\nbeyond the G protein paradigm","volume":"145","author":"Hall","year":"1999","journal-title":"J. Cell Biol."},{"key":"2026081804441346200_cit2","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/nrm908","article-title":"Seven-transmembrane\nreceptors","volume":"3","author":"Pierce","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2026081804441346200_cit3","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1146\/annurev-biochem-060614-033910","article-title":"The Molecular Basis\nof G Protein-Coupled Receptor Activation","volume":"87","author":"Weis","year":"2018","journal-title":"Annu.\nRev. Biochem."},{"key":"2026081804441346200_cit4","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1124\/mol.63.6.1256","article-title":"The G-protein-coupled\nreceptors in the human genome form five main families. Phylogenetic\nanalysis, paralogon groups, and fingerprints","volume":"63","author":"Fredriksson","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"2026081804441346200_cit5","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/1756-0500-1-67","article-title":"GPCRTree: online\nhierarchical classification of GPCR function","volume":"1","author":"Davies","year":"2008","journal-title":"BMC Res. Notes"},{"key":"2026081804441346200_cit6","doi-asserted-by":"publisher","first-page":"2471","DOI":"10.1093\/molbev\/msr061","article-title":"Independent HHsearch,\nNeedleman-Wunsch-based, and motif\nanalyses reveal the overall hierarchy for most of the G protein-coupled\nreceptor families","volume":"28","author":"Nordstrom","year":"2011","journal-title":"Mol. Biol. Evol."},{"key":"2026081804441346200_cit7","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.tibs.2018.11.011","article-title":"New Binding\nSites, New Opportunities for GPCR Drug Discovery","volume":"44","author":"Chan","year":"2019","journal-title":"Trends Biochem. Sci."},{"key":"2026081804441346200_cit8","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.cell.2020.03.003","article-title":"Impact\nof GPCR Structures\non Drug Discovery","volume":"181","author":"Congreve","year":"2020","journal-title":"Cell"},{"key":"2026081804441346200_cit9","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1016\/j.bpj.2017.04.051","article-title":"G Protein-Coupled\nReceptors Contain\nTwo Conserved Packing Clusters","volume":"112","author":"Sanchez-Reyes","year":"2017","journal-title":"Biophys. J."},{"key":"2026081804441346200_cit10","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41594-017-0011-7","article-title":"Structure\nand dynamics of GPCR signaling\ncomplexes","volume":"25","author":"Hilger","year":"2018","journal-title":"Nat. Struct Mol. 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Sci."},{"key":"2026081804441346200_cit15","doi-asserted-by":"publisher","first-page":"2584","DOI":"10.1073\/pnas.0307882100","article-title":"The human olfactory\nreceptor gene\nfamily","volume":"101","author":"Malnic","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081804441346200_cit16","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1007\/s003350010196","article-title":"The olfactory receptor\ngene superfamily: data mining,\nclassification, and nomenclature","volume":"11","author":"Glusman","year":"2000","journal-title":"Mamm. 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A."},{"key":"2026081804441346200_cit19","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000182RR","article-title":"Conserved\nC-terminal motifs in odorant receptors instruct their cell surface\nexpression and cAMP signaling","volume":"35","author":"Kotthoff","year":"2021","journal-title":"FASEB J."},{"key":"2026081804441346200_cit20","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1002\/pro.2717","article-title":"G protein-coupled\nodorant receptors: From sequence to structure","volume":"24","author":"de\nMarch","year":"2015","journal-title":"Protein Sci."},{"key":"2026081804441346200_cit21","doi-asserted-by":"publisher","first-page":"8611","DOI":"10.1021\/jacs.5b04659","article-title":"Conserved\nResidues Control Activation of Mammalian G Protein-Coupled Odorant\nReceptors","volume":"137","author":"de\nMarch","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"2026081804441346200_cit22","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1110\/ps.03296404","article-title":"Prediction\nof the odorant binding\nsite of olfactory receptor proteins by human-mouse comparisons","volume":"13","author":"Man","year":"2004","journal-title":"Protein Sci."},{"key":"2026081804441346200_cit23","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1007\/s00018-018-2996-4","article-title":"Mammalian class I odorant receptors exhibit a conserved\nvestibular-binding pocket","volume":"76","author":"Bushdid","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"2026081804441346200_cit24","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1002\/anie.201103980","article-title":"Prediction\nof a ligand-binding niche within a human olfactory receptor by combining\nsite-directed mutagenesis with dynamic homology modeling","volume":"51","author":"Gelis","year":"2012","journal-title":"Angew. Chem., Int. Ed. Engl."},{"key":"2026081804441346200_cit25","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1021\/acscentsci.1c01495","article-title":"Large-Scale G Protein-Coupled Olfactory\nReceptor-Ligand\nPairing","volume":"8","author":"Cong","year":"2022","journal-title":"ACS Cent Sci."},{"key":"2026081804441346200_cit26","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/1749-8104-3-22","article-title":"Expressing exogenous\nfunctional odorant receptors in cultured olfactory sensory neurons","volume":"3","author":"Chen","year":"2008","journal-title":"Neural development"},{"key":"2026081804441346200_cit27","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1093\/chemse\/bjw117","article-title":"The Broadly Tuned Odorant Receptor\nOR1A1 is Highly Selective for 3-Methyl-2,4-nonanedione, a Key Food\nOdorant in Aged Wines, Tea, and Other Foods","volume":"42","author":"Geithe","year":"2017","journal-title":"Chemical senses"},{"key":"2026081804441346200_cit28","doi-asserted-by":"publisher","first-page":"6018","DOI":"10.1523\/JNEUROSCI.21-16-06018.2001","article-title":"Molecular bases of odor discrimination: Reconstitution\nof olfactory receptors that recognize overlapping sets of odorants","volume":"21","author":"Kajiya","year":"2001","journal-title":"J. Neurosci."},{"key":"2026081804441346200_cit29","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/S0092-8674(00)80581-4","article-title":"Combinatorial receptor\ncodes for odors","volume":"96","author":"Malnic","year":"1999","journal-title":"Cell"},{"key":"2026081804441346200_cit30","doi-asserted-by":"publisher","first-page":"9179","DOI":"10.1523\/JNEUROSCI.1282-11.2011","article-title":"A Large-Scale Analysis\nof Odor Coding in the Olfactory Epithelium","volume":"31","author":"Nara","year":"2011","journal-title":"J. Neurosci."},{"key":"2026081804441346200_cit31","doi-asserted-by":"publisher","first-page":"ra9","DOI":"10.1126\/scisignal.2000016","article-title":"Odor coding by a\nMammalian receptor repertoire","volume":"2","author":"Saito","year":"2009","journal-title":"Sci. Signal"},{"key":"2026081804441346200_cit32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002821","article-title":"Functional\nevolution of mammalian\nodorant receptors","volume":"8","author":"Adipietro","year":"2012","journal-title":"PLoS Genet"},{"key":"2026081804441346200_cit33","doi-asserted-by":"publisher","first-page":"150002","DOI":"10.1038\/sdata.2015.2","article-title":"Human olfactory\nreceptor responses to odorants","volume":"2","author":"Mainland","year":"2015","journal-title":"Scientific data"},{"key":"2026081804441346200_cit34","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1093\/chemse\/bjw118","article-title":"OR2M3: A Highly\nSpecific and Narrowly Tuned Human Odorant\nReceptor for the Sensitive Detection of Onion Key Food Odorant 3-Mercapto-2-methylpentan-1-ol","volume":"42","author":"Noe","year":"2017","journal-title":"Chemical senses"},{"key":"2026081804441346200_cit35","doi-asserted-by":"publisher","first-page":"131680","DOI":"10.1016\/j.foodchem.2021.131680","article-title":"The key food odorant receptive range\nof broadly tuned receptor OR2W1","volume":"375","author":"Haag","year":"2022","journal-title":"Food Chem."},{"key":"2026081804441346200_cit36","doi-asserted-by":"publisher","first-page":"4205","DOI":"10.1007\/s00018-012-1116-0","article-title":"How broadly\ntuned olfactory receptors equally recognize their agonists. Human\nOR1G1 as a test case","volume":"69","author":"Charlier","year":"2012","journal-title":"Cell. Mol. Life Sci."},{"key":"2026081804441346200_cit37","doi-asserted-by":"publisher","first-page":"11546","DOI":"10.3390\/ijms222111546","article-title":"Machine Learning\nAssisted Approach for Finding Novel High Activity Agonists of Human\nEctopic Olfactory Receptors","volume":"22","author":"Jabeen","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"2026081804441346200_cit38","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-809324-5.24147-3","article-title":"Toward\nthe Digitalization of\nOlfaction","volume-title":"Reference Module in Neuroscience\nand Biobehavioral Psychology","author":"Di Pizio","year":"2021"},{"key":"2026081804441346200_cit39","doi-asserted-by":"publisher","first-page":"1698","DOI":"10.1124\/pharmrev.120.000246","article-title":"Structure-Based\nVirtual Screening for Ligands of G Protein-Coupled Receptors: What\nCan Molecular Docking Do for You?","volume":"73","author":"Ballante","year":"2021","journal-title":"Pharmacol\nRev."},{"key":"2026081804441346200_cit40","doi-asserted-by":"publisher","first-page":"13346","DOI":"10.1021\/acs.jafc.8b04471","article-title":"Molecular\nBasis of Mammalian Odor Discrimination: A Status Report","volume":"66","author":"Block","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"2026081804441346200_cit41","doi-asserted-by":"publisher","first-page":"2235","DOI":"10.1021\/acs.jpclett.8b00633","article-title":"Agonists of G-Protein-Coupled Odorant Receptors Are\nPredicted from Chemical Features","volume":"9","author":"Bushdid","year":"2018","journal-title":"J. Phys. Chem.\nLett."},{"key":"2026081804441346200_cit42","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s42003-019-0384-8","article-title":"Computational modeling of the olfactory receptor Olfr73 suggests\na molecular basis for low potency of olfactory receptor-activating\ncompounds","volume":"2","author":"Yuan","year":"2019","journal-title":"Commun. Biol."},{"key":"2026081804441346200_cit43","doi-asserted-by":"publisher","first-page":"2157","DOI":"10.1007\/s00018-019-03279-y","article-title":"Copper-mediated thiol potentiation\nand mutagenesis-guided\nmodeling suggest a highly conserved copper-binding motif in human\nOR2M3","volume":"77","author":"Haag","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"2026081804441346200_cit44","doi-asserted-by":"publisher","first-page":"3494","DOI":"10.1016\/j.csbj.2020.11.007","article-title":"Homology modeling in\nthe time of collective and artificial intelligence","volume":"18","author":"Hameduh","year":"2020","journal-title":"Comput. Struct Biotechnol J."},{"key":"2026081804441346200_cit45","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1126\/science.abj8754","article-title":"Accurate prediction\nof protein structures and interactions using a three-track neural\nnetwork","volume":"373","author":"Baek","year":"2021","journal-title":"Science"},{"key":"2026081804441346200_cit46","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein\nstructure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"2026081804441346200_cit47","doi-asserted-by":"publisher","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database:\nmassively expanding the structural coverage of protein-sequence space\nwith high-accuracy models","volume":"50","author":"Varadi","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"2026081804441346200_cit48","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/s41586-021-03828-1","article-title":"Highly accurate\nprotein structure prediction for the\nhuman proteome","volume":"596","author":"Tunyasuvunakool","year":"2021","journal-title":"Nature"},{"key":"2026081804441346200_cit49","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1038\/s41594-022-00849-w","article-title":"A structural\nbiology community assessment of AlphaFold2\napplications","volume":"29","author":"Akdel","year":"2022","journal-title":"Nat. Struct Mol. Biol."},{"key":"2026081804441346200_cit50","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax0396","article-title":"A transcriptomic\natlas of mammalian olfactory mucosae reveals an evolutionary influence\non food odor detection in humans","volume":"5","author":"Saraiva","year":"2019","journal-title":"Sci. Adv."},{"key":"2026081804441346200_cit51","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202100224R","article-title":"An evolutionary\nconserved olfactory receptor for foodborne and semiochemical alkylpyrazines","volume":"35","author":"Marcinek","year":"2021","journal-title":"FASEB J."},{"key":"2026081804441346200_cit52","doi-asserted-by":"publisher","first-page":"574082","DOI":"10.3389\/fphys.2020.574082","article-title":"The Sensing\nLiver: Localization and Ligands for Hepatic Murine Olfactory and Taste\nReceptors","volume":"11","author":"Kurtz","year":"2020","journal-title":"Front Physiol"},{"key":"2026081804441346200_cit53","doi-asserted-by":"publisher","first-page":"2050","DOI":"10.1111\/asj.12876","article-title":"Retort beef aroma that gives preferable\nproperties\nto canned beef products and its aroma components","volume":"88","author":"Migita","year":"2017","journal-title":"Anim Sci. J."},{"key":"2026081804441346200_cit54","doi-asserted-by":"publisher","first-page":"551","DOI":"10.5650\/jos.ess19014","article-title":"Characterization\nof the Volatile\nCompounds and Taste Attributes of Sesame Pastes Processed at Different\nTemperatures","volume":"68","author":"Hou","year":"2019","journal-title":"J. Oleo Sci."},{"key":"2026081804441346200_cit55","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1007\/s10719-016-9694-y","article-title":"Pathways of the\nMaillard reaction under physiological\nconditions","volume":"33","author":"Henning","year":"2016","journal-title":"Glycoconj J."},{"key":"2026081804441346200_cit56","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1111\/nph.12800","article-title":"Discovery\nof pyrazines as pollinator sex pheromones and orchid semiochemicals:\nimplications for the evolution of sexual deception","volume":"203","author":"Bohman","year":"2014","journal-title":"New Phytol"},{"key":"2026081804441346200_cit57","doi-asserted-by":"publisher","first-page":"2595","DOI":"10.1038\/s41598-018-20953-6","article-title":"Pyrazines from bacteria\nand ants: convergent chemistry within an ecological niche","volume":"8","author":"Silva-Junior","year":"2018","journal-title":"Sci. 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