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We recently described allosteric modulators (AMs) of \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR that preferentially enhance isoproterenol\u2010mediated \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR\u2010G\u03b1s signalling in ASM. Orthosteric \u03b2\u2010agonists differ in efficacy, kinetics and signalling bias, and how this diversity shapes allosteric modulation of \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      ARs remains unclear. We investigated whether AMs could selectively modulate \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR\u2010G\u03b1s signalling and bronchodilation in response to endogenous and clinically relevant \u03b2\u2010agonists.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      The effects of a positive AM (PAM37) and two negative AMs (NAM36 and NAM42) were examined on \u03b2\u2010agonist\u2010induced G\u03b1s and \u03b2\u2010arrestin recruitment and downstream signalling (cAMP, PKA and ERK) in HEK293 cells expressing \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      ARs and primary human ASM cells. Bronchodilation was assessed using murine precision\u2010cut lung slices and in vivo lung mechanics. Molecular dynamics (MD) simulations were performed to delineate structural determinants of agonist\u2010dependent AM activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      PAM37 enhanced, whereas NAMs attenuated \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR\u2010G\u03b1s coupling, signalling and bronchodilation with no effect on \u03b2\u2010arrestin\u2010ERK signalling, establishing G\u03b1s signalling and functional bias. AM effects differed in magnitude and kinetic profiles across \u03b2\u2010agonists, with fenoterol uniquely resistant to modulation. MD simulations revealed that fenoterol stabilizes a quasi\u2010inactive \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR conformation characterized by an TM6 shift that occludes the allosteric pocket, providing a structural basis for its resistance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>\n                      These findings establish orthosteric ligand\u2010dependent allostery as a fundamental feature of \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR pharmacology. PAM37 represents a tool to selectively enhance bronchodilation by \u03b2\u2010agonists in asthma.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70513","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:11:17Z","timestamp":1780877477000},"page":"5315-5335","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Agonist\u2010specific conformational dynamics at the \u03b2\n                    <sub>2<\/sub>\n                    \u2010adrenoceptor dictate allosteric modulation of G\u03b1s signalling and bronchodilation"],"prefix":"10.1111","volume":"183","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4201-6532","authenticated-orcid":false,"given":"Sushrut D.","family":"Shah","sequence":"first","affiliation":[{"name":"Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5002-0921","authenticated-orcid":false,"given":"Joshua","family":"Richard","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4612-8021","authenticated-orcid":false,"given":"Suvankar","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Computer\u2010Aided Drug Design Center University of Maryland  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7143-5677","authenticated-orcid":false,"given":"Jillian","family":"Jerwick","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7937-3704","authenticated-orcid":false,"given":"Joice T.","family":"Gavali","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8452-5880","authenticated-orcid":false,"given":"Raymond B.","family":"Penn","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8287-6804","authenticated-orcid":false,"suffix":"Jr","given":"Alexander D.","family":"MacKerell","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Computer\u2010Aided Drug Design Center University of Maryland  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6187-5332","authenticated-orcid":false,"given":"Deepak A.","family":"Deshpande","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,7]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI167337"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.118.111948"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70230"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70234"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_12_7_1","unstructured":"Asthma GIf. 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