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Adv."],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:p>\n                    The third-generation antipsychotic cariprazine is a low-efficacy partial agonist of the dopamine D\n                    <jats:sub>3<\/jats:sub>\n                    receptor (D\n                    <jats:sub>3<\/jats:sub>\n                    R). Here, we report the cryo\u2013electron microscopy structure of cariprazine bound to D\n                    <jats:sub>3<\/jats:sub>\n                    R, establishing a framework for understanding ligand recognition in this receptor. We further determine structures of D\n                    <jats:sub>3<\/jats:sub>\n                    R in complex with a series of cariprazine derivatives spanning inverse agonists to high-efficacy partial agonists. Integration of structural data with pharmacological profiling and molecular dynamics simulations reveals how subtle chemical modifications translate into distinct functional outcomes. Determinants distinguishing agonism from inverse agonism are well defined, whereas differences among partial agonists arise from small positional shifts of the ligand within the orthosteric binding site. In contrast, the extended binding site primarily modulates ligand stability, affinity, and receptor selectivity. These findings establish a mechanistic link between bitopic ligand architecture and receptor activation, providing a \u201cligand-centric\u201d view of D\n                    <jats:sub>3<\/jats:sub>\n                    R signaling. Leveraging these principles, we designed and validated cariprazine derivatives with enhanced D\n                    <jats:sub>3<\/jats:sub>\n                    \/D\n                    <jats:sub>2<\/jats:sub>\n                    selectivity and partial agonist activity. Together, this work provides a structural and pharmacological blueprint for the rational design of D\n                    <jats:sub>3<\/jats:sub>\n                    R-targeting ligands with tailored efficacy and therapeutic profiles.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aef7411","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:58:31Z","timestamp":1787939911000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["The structure of the dopamine D\n                    <sub>3<\/sub>\n                    receptor bound to cariprazine reveals principles for partial agonists with designed pharmacology"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3898-5035","authenticated-orcid":true,"given":"Eliane","family":"Hadas Yardeni","sequence":"first","affiliation":[{"name":"Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel."},{"name":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6664-3872","authenticated-orcid":true,"given":"D\u00f3ra Judit","family":"Kiss","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary."},{"name":"National Laboratory of Drug Research and Development, Budapest, Hungary."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5765-4342","authenticated-orcid":true,"given":"Julie","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen\u2019s Medical Centre, University of Nottingham, Nottingham, UK."},{"name":"Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, Nottingham, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1343-2481","authenticated-orcid":true,"given":"Keshet","family":"Shavit","sequence":"additional","affiliation":[{"name":"Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e9nes","family":"Szepesi Kov\u00e1cs","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary."},{"name":"National Laboratory of Drug Research and Development, Budapest, Hungary."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8463-4219","authenticated-orcid":true,"given":"Attila","family":"Egyed","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, 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Biochemistry and Molecular Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9065-4072","authenticated-orcid":true,"given":"Amy Hauck","family":"Newman","sequence":"additional","affiliation":[{"name":"Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse\u2013Intramural Research Program, National Institutes of Health, Baltimore, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7361-7875","authenticated-orcid":true,"given":"J. 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