{"id":3287,"date":"2026-01-02T15:50:52","date_gmt":"2026-01-02T20:50:52","guid":{"rendered":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/?p=3287"},"modified":"2026-01-02T15:50:52","modified_gmt":"2026-01-02T20:50:52","slug":"new-paper-on-mechanism-of-tethered-agonist-binding-to-an-adhesion-g-protein-coupled-receptor","status":"publish","type":"post","link":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2026\/01\/new-paper-on-mechanism-of-tethered-agonist-binding-to-an-adhesion-g-protein-coupled-receptor\/","title":{"rendered":"New paper on &#8220;Mechanism of Tethered Agonist Binding to an Adhesion G-Protein-Coupled Receptor&#8221;"},"content":{"rendered":"<p>Congratulations to Keya for a first-authored paper published in The Journal of Physical Chemistry B on \u201c<strong><a class=\"gsc_a_at\" href=\"https:\/\/pubs.acs.org\/doi\/full\/10.1021\/acs.jpcb.5c05305\">Mechanism of Tethered Agonist Binding to an Adhesion G-Protein-Coupled Receptor<\/a><\/strong>&#8220;!<\/p>\n<div id=\"Abstract\" class=\"article_abstract-title\">\n<h2>Abstract<\/h2>\n<div class=\"article__copy\"><\/div>\n<\/div>\n<div id=\"abstractBox\" class=\"article_abstract-content hlFld-Abstract\">\n<figure id=\"_i1\" class=\"article__inlineFigure article_abstract-img\" data-index=\"0\"><button class=\"figure-viewer__trigger\" aria-label=\"open figure viewer\"><img decoding=\"async\" id=\"tgr1\" class=\"inline-fig internalNav\" src=\"https:\/\/pubs.acs.org\/cms\/10.1021\/acs.jpcb.5c05305\/asset\/images\/medium\/jp5c05305_0006.gif\" alt=\"\" \/><\/button><\/figure>\n<p class=\"articleBody_abstractText\">Adhesion G-protein-coupled receptors (ADGRs) contain a GPCR autoproteolysis-inducing (GAIN) domain that is proximal to the receptor N-terminus and undergoes autoproteolysis at a highly conserved GPCR proteolysis site to generate the N-terminal fragment and transmembrane C-terminal fragment. Dissociation of the N-terminal fragment reveals a peptide tethered agonist (TA) that is responsible for the activation of the ADGRs. The inactive complete ADGRs contain the encrypted TA that assumes a \u03b2-strand configuration within the GAIN domain, which is markedly different from the U-shaped \u03b1-helical configuration of TA in the active cryo-EM structures of ADGRs. However, how the TA dramatically changes its configuration and binds to the ADGR C-terminal fragment remains unknown. In this study, we have performed all-atom enhanced sampling simulations using a novel Peptide Gaussian-accelerated Molecular Dynamics (Pep-GaMD) method for the binding of TA to ADGRD1. The Pep-GaMD simulations captured spontaneous binding of the TA into the orthosteric pocket of ADGRD1 and its large conformational transition from the extended \u03b2-strand to the U-shaped \u03b1-helical configuration. We were able to identify important low-energy conformations of the TA in the binding pathway, as well as different active and inactive states of ADGRD1, in the presence and absence of the G<sub>s<\/sub>-protein. Therefore, our Pep-GaMD simulations have revealed the dynamic mechanism of the TA binding to an ADGR, which will facilitate the rational design of the peptide regulators of ADGRs.<\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Congratulations to Keya for a first-authored paper published in The Journal of Physical Chemistry B on \u201cMechanism of Tethered Agonist Binding to an Adhesion G-Protein-Coupled Receptor&#8220;! Abstract Adhesion G-protein-coupled receptors (ADGRs) contain a GPCR autoproteolysis-inducing (GAIN) domain that is proximal to the receptor N-terminus and undergoes autoproteolysis at a highly conserved GPCR proteolysis site to &hellip; <a href=\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2026\/01\/new-paper-on-mechanism-of-tethered-agonist-binding-to-an-adhesion-g-protein-coupled-receptor\/\" aria-label=\"Read more about New paper on &#8220;Mechanism of Tethered Agonist Binding to an Adhesion G-Protein-Coupled Receptor&#8221;\">Read more<\/a><\/p>\n","protected":false},"author":115433,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"layout":"","cellInformation":"","apiCallInformation":"","footnotes":"","_links_to":"","_links_to_target":""},"categories":[1],"tags":[],"class_list":["post-3287","post","type-post","status-publish","format-standard","hentry","category-news","odd"],"acf":[],"featured_image":false,"featured_image_medium":false,"featured_image_medium_large":false,"featured_image_large":false,"featured_image_thumbnail":false,"featured_image_alt":false,"category_details":[{"name":"News","link":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/category\/news\/"}],"tag_details":[],"_links_to":[],"_links_to_target":[],"_links":{"self":[{"href":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-json\/wp\/v2\/posts\/3287","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-json\/wp\/v2\/users\/115433"}],"replies":[{"embeddable":true,"href":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-json\/wp\/v2\/comments?post=3287"}],"version-history":[{"count":1,"href":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-json\/wp\/v2\/posts\/3287\/revisions"}],"predecessor-version":[{"id":3288,"href":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-json\/wp\/v2\/posts\/3287\/revisions\/3288"}],"wp:attachment":[{"href":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-json\/wp\/v2\/media?parent=3287"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-json\/wp\/v2\/categories?post=3287"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-json\/wp\/v2\/tags?post=3287"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}