{"id":25674,"date":"2025-11-05T08:00:00","date_gmt":"2025-11-05T16:00:00","guid":{"rendered":"https:\/\/dornsife.usc.edu\/news\/?p=25674"},"modified":"2026-03-04T16:56:02","modified_gmt":"2026-03-05T00:56:02","slug":"mu-opioid-receptor-structural-change-revealed-by-cryo-em","status":"publish","type":"post","link":"https:\/\/dornsife.usc.edu\/news\/stories\/mu-opioid-receptor-structural-change-revealed-by-cryo-em\/","title":{"rendered":"A path to safer painkillers \u2013 revealed by freezing opioids and their protein receptors in motion"},"content":{"rendered":"\n\n\n    \n                                          \n\n  \n    \n\n\n\n\n\n\n<div\n  class=\"cc--component-container cc--article-hero \"\n\n  \n  \n  \n  \n  \n  \n  >\n  <div class=\"c--component c--article-hero\"\n    \n      >\n\n    \n<div class=\"inner-wrapper\">\n          \n<div class=\"f--field f--image\">\n\n    \n    \n    \n    \n    \n    \n              \n      <img\n                            data-src=\"https:\/\/dornsife.usc.edu\/news\/wp-content\/uploads\/sites\/7\/2025\/11\/gati-mu-opioid-receptor-top-768x432.jpg\"\n          data-srcset=\"https:\/\/dornsife.usc.edu\/news\/wp-content\/uploads\/sites\/7\/2025\/11\/gati-mu-opioid-receptor-top-1920x1080.jpg 1920w,https:\/\/dornsife.usc.edu\/news\/wp-content\/uploads\/sites\/7\/2025\/11\/gati-mu-opioid-receptor-top-1280x720.jpg 1280w,https:\/\/dornsife.usc.edu\/news\/wp-content\/uploads\/sites\/7\/2025\/11\/gati-mu-opioid-receptor-top-768x432.jpg 768w\"          data-sizes=\"(min-width:1200px) 75vw, (min-width:768px) 83vw, 100vw\"          class=\"lazyload\"\n        \n                  alt=\"Illustration of mu-opioid receptors embedded in cell membrane, with one releasing a G protein\"\n        \n        \n                                      \/>\n\n    \n    \n  \n  \n\n<\/div>\n  \n      <div class=\"image-caption\">\n          \n<div class=\"f--field f--description\">\n\n    \n  Two different versions of the mu-opioid receptor within a cellular membrane illustrate how the receptor changes its form to send a signal into the cell. (Illustration: Courtesy of Saif Khan and Vishwang Gowariker.)\n\n\n<\/div>\n    <\/div>\n  \n  <div class=\"text-wrapper\">\n          <nav aria-label=\"Breadcrumb\" class=\"breadcrumbs\">\n        <ul>\n                      <li><a href=\"\/news\/stories\/\">News<\/a><\/li>\n                      <li><a href=\"\/news\/stories\/\/?category=science-and-technology\">Science and Technology<\/a><\/li>\n                  <\/ul>\n      <\/nav>\n    \n              \n<div class=\"f--field f--page-title\">\n\n    \n  <h1>A path to safer painkillers \u2013 revealed by freezing opioids and their protein receptors in motion<\/h1>\n\n\n<\/div>\n    \n          <div class=\"subtitle\">\n            \n<div class=\"f--field f--description\">\n\n    \n  With near-atomic precision, a USC Dornsife team of scientists visualized for the first time how opioids such as loperamide and the antidote naloxone engage a key brain receptor, offering insight that could lead to better pain treatments and improved overdose reversal.\n\n\n<\/div>\n      <\/div>\n    \n           <strong class=\"author-field\"><span >By<\/span><a href=\"mailto:communication@dornsife.usc.edu\">USC Dornsife News<\/a><\/strong>\n    \n          <span class=\"post-date-field\">November 5, 2025<\/span>\n      <\/div>\n<\/div>\n\n\n  <\/div><\/div>\n\n  \n    \n\n\n\n\n\n\n<div\n  class=\"cc--component-container cc--social-share \"\n\n  \n  \n  \n  \n  \n  \n  >\n  <div class=\"c--component c--social-share\"\n    \n      >\n\n    \n  <div class=\"content-wrapper\">\n    <span class=\"a2a_kit a2a_kit_size_32 addtoany_list\" style=\"line-height: 32px;\">\n      <span class=\"title\">\n        Share\n      <\/span>\n                        <a class=\"a2a_button_copy_link\" target=\"_blank\" href=\"\/#copy_link\" rel=\"nofollow noopener\" title=\"Link\">\n            <span class=\"a2a_svg a2a_s__default a2a_s_copy_link\">\n              <svg height=\"19\" viewBox=\"0 0 19 19\" width=\"19\" 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cc--article-highlights \"\n\n  \n  \n  \n  \n  \n  \n  >\n  <div class=\"c--component c--article-highlights\"\n    \n      >\n\n    \n<div class=\"inner-wrapper\">\n          \n<div class=\"f--field f--section-title\">\n\n    \n  <h2>\n          Key findings:\n      <\/h2>\n\n\n<\/div>\n    \n      <ul>\n              <li><p>Scientists captured six high-resolution \u201csnapshots\u201d showing how opioids activate \u2014 and how antidotes like Narcan block \u2014 a key brain receptor that controls pain and addiction.<\/p>\n<\/li>\n              <li><p>The study provides the first view of Narcan\u2019s lifesaving action at the molecular level.<\/p>\n<\/li>\n              <li><p>The discovery offers new avenues for developing painkillers that relieve pain without triggering addiction or dangerous side effects.<\/p>\n<\/li>\n          <\/ul>\n  <\/div>\n  \n\n  <\/div><\/div>\n\n\n\n\n  \n    \n\n\n\n\n\n\n<div\n  class=\"cc--component-container cc--rich-text \"\n\n  \n  \n  \n  \n  \n  \n  >\n  <div class=\"c--component c--rich-text\"\n    \n      >\n\n    \n      \n<div class=\"f--field f--wysiwyg\">\n\n    \n  <p>Scientists have known for decades that opioids relieve pain by binding to molecular switches in the brain called mu-opioid (pronounced \u201cmew-opioid\u201d) receptors. What they didn\u2019t know \u2014 until now \u2014 was exactly what happens next.<\/p>\n<p>A team led by biologists at the USC Dornsife College of Letters, Arts and Sciences, in collaboration with the <a href=\"https:\/\/keck.usc.edu\/\" target=\"_blank\" rel=\"noopener\">Keck School of Medicine of USC<\/a>, has captured those receptors mid-action, creating the molecular equivalent of a slow-motion movie. <a href=\"https:\/\/urldefense.com\/v3\/__https:\/www.nature.com\/articles\/s41586-025-09677-6__;!!LIr3w8kk_Xxm!unOZQPsb4wcRirfy2gzCzVnnYwcASpF8IxDydf4FIhQv6tO-qbSlLyKDkKQKx5mJQ1eYCvZWZw$\" target=\"_blank\" rel=\"noopener\">Their discovery<\/a>, published this week in <em>Nature<\/em> and supported by the National Institutes of Health, could help scientists design painkillers that aren\u2019t as addictive and develop longer-acting overdose antidotes like naloxone, better known by its brand name Narcan.<\/p>\n<p>\u201cIt\u2019s a little like watching an engine run in super slow motion,\u201d said study corresponding author <a href=\"https:\/\/dornsife.usc.edu\/profile\/cornelius-gati\/\">Cornelius Gati<\/a>, assistant professor of biological sciences, chemistry, and quantitative and computational biology at USC Dornsife. \u201cWe can finally see which parts move when an opioid drug binds to the receptor \u2014 and how Narcan literally jams the mechanism before the process can start.\u201d<\/p>\n<h2>An opioid molecular movie in motion<\/h2>\n<p>To capture these fleeting molecular events, Gati\u2019s team used cryo-electron microscopy (cryo-EM), a technique that flash-freezes molecules and then images them at near-atomic resolution. The method allowed the researchers to see how the receptor and its partner molecule, a \u201cG protein\u201d that transmits signals inside the cell, change shape when an opioid binds and activates the receptor.<\/p>\n<p>The team conducted their experiments using USC\u2019s in-house <a href=\"https:\/\/dornsife.usc.edu\/news\/stories\/cryogenic-electron-microscopy-facility-opens\/\">cryo-EM facility<\/a> housed in the <a href=\"https:\/\/michelson.usc.edu\/\" target=\"_blank\" rel=\"noopener\">USC Michelson Center for Convergent Bioscience<\/a>.<\/p>\n<p>\u201cBefore this, scientists only had two still images of this receptor \u2014 one off and one on,\u201d said Saif Khan, the study\u2019s first author and a PhD student in Gati\u2019s lab. \u201cNow we can see everything that happens in between. It\u2019s like going from two snapshots to a flipbook that finally reveals the full motion.\u201d<\/p>\n<p>Within a set of eight unique 3D models and 16 cryo-EM 3D images, the team captured six different receptor states, each representing a distinct step in how opioid drugs and their antidotes affect the function of their receptor.<\/p>\n<h2>How opioids turn on \u2014 and Narcan turns off \u2014 the signal<\/h2>\n<p>The mu-opioid receptor is part of a large family of proteins called G protein-coupled receptors (GPCRs), which help regulate everything from pain to mood, heartrate and metabolism. When an opioid drug binds to the receptor, it triggers the release of a small molecule called GDP from its G protein, setting off a cascade of signals that activate the body\u2019s pain-relief pathways.<\/p>\n<p>But when that signaling goes too far, it can slow breathing and produce euphoria \u2014 effects that underlie both overdose and addiction.<\/p>\n<p>The researchers found that different drugs influence this process in distinct ways. Loperamide, a powerful opioid that doesn\u2019t cross the blood-brain barrier, shifts the receptor into a structural shape that quickly releases GDP \u2014 essentially flipping the \u201con\u201d switch. In contrast, Narcan locks the receptor in what Gati\u2019s team calls a \u201clatent\u201d state, like pressing a molecular pause button before GDP can be released.<\/p>\n<p>\u201cScientists thought that drugs like Narcan stop the receptor from talking to its G protein,\u201d said Khan. \u201cWe now see that the conversation starts \u2014 it just never finishes because Narcan interrupts it.\u201d<\/p>\n<h2>Opioid receptor breakthrough points to new drug discovery paths<\/h2>\n<p>Despite growing awareness of their dangerous side effects, opioids remain widely prescribed, with about 125 million prescriptions filled in the U.S. in 2023, according to the U.S. Centers for Disease Control and Prevention. More than 80,000 Americans died from opioid overdoses that year.<\/p>\n<p>Narcan is the standard lifesaving antidote used by first responders, but with new synthetic opioids like fentanyl \u2014 hundreds of times more potent than morphine \u2014 patients may not always respond quickly enough to it. Because current treatments wear off faster than the opioids they counteract, patients often require multiple doses.<\/p>\n<p>Knowing precisely how Narcan interacts with the receptor could guide chemists in designing longer-lasting or faster-acting antidotes, while understanding the receptor\u2019s step-by-step mechanics could help fine-tune opioid painkillers so they relieve pain without causing dangerous side effects such as difficulty breathing.<\/p>\n<p>\u201cIf we can design drugs that activate only part of this molecular machinery,\u201d Gati said, \u201cwe might be able to keep the good \u2014 pain relief \u2014 and lose the bad, like addiction and respiratory depression.\u201d<\/p>\n<p>Gati added that the implications extend far beyond opioids. The mu-opioid receptor belongs to one of the largest families of drug targets in the human body, and roughly a third of all prescription medicines, involved in everything from mood regulation to metabolism, act on these GPCRs.<\/p>\n<p>\u201cThis is a template for understanding how an entire class of receptors works,\u201d he said. \u201cIf we can map these molecular movements for opioids, we can apply the same principles to designing better drugs for heart disease, depression and diabetes.\u201d<\/p>\n<p>The images Gati\u2019s team produced are among the most detailed views ever obtained for an opioid receptor complex. Each snapshot revealed subtle shifts in how the receptor grips the G protein, releases GDP, and opens the pathway that triggers activation.<\/p>\n<p>The researchers also used computer simulations to watch the molecules move in real time, confirming that the transitions captured in frozen form match the receptor\u2019s natural behavior.<\/p>\n<p>\u201cProteins are like tiny molecular machines,\u201d said Khan. \u201cAnd the best way to understand how a machine works is to watch it in motion. That\u2019s what we\u2019ve finally been able to do \u2014 see this receptor operating at the nanoscale, in real time.\u201d<\/p>\n<h2>A new chapter in the opioid story<\/h2>\n<p>While the findings won\u2019t solve the opioid crisis overnight, they offer something the field has long lacked: a detailed roadmap of how opioid drugs and antidotes work from the inside out.<\/p>\n<p>\u201cThis is basic science, but it\u2019s the kind of basic science that can transform medicine,\u201d said Gati, who also holds a joint appointment in pharmacology and pharmaceutical sciences at the <a href=\"https:\/\/mann.usc.edu\/\" target=\"_blank\" rel=\"noopener\">USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences<\/a>. \u201cBy understanding these receptors in such detail, we can finally start designing drugs that are as smart as the molecules they target.\u201d<\/p>\n<h2>About the study<\/h2>\n<p>In addition to Gati and Khan, study authors include Aaliyah Tyson, Mohsen Ranjbar, Jaskaran Singh and Gye Won Han of USC Dornsife, and Zixin Zhang of Keck School of Medicine of USC.<\/p>\n<p>The research was supported by National Institutes of Health grant R01AT012075.<\/p>\n\n\n\n<\/div>\n\n\n  <\/div><\/div>\n\n\n\n  \n        \n  \n    \n\n\n\n\n\n\n<div\n  class=\"cc--component-container cc--article-related-stories \"\n\n  \n  \n  \n  \n  \n  \n  >\n  <div class=\"c--component c--article-related-stories\"\n    \n      >\n\n    \n  <div class=\"inner-wrapper\">\n              \n<div class=\"f--field f--section-title\">\n\n    \n  <h2>\n          Related Articles\n      <\/h2>\n\n\n<\/div>\n    \n                  <article>\n              \n<div 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risk<\/a>\n      <\/h3>\n\n\n<\/div>\n        <\/article>\n            <\/div>\n\n\n  <\/div><\/div>\n","protected":false},"excerpt":{"rendered":"<p>With near-atomic precision, a USC Dornsife team of scientists visualized for the first time how opioids and the antidote Narcan engage a key brain receptor, offering insight that could lead to improved pain treatments and overdose reversal.<\/p>\n","protected":false},"author":14,"featured_media":25678,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[26,16],"tags":[88,113,78,202,86,60],"class_list":["post-25674","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-health","category-science-and-technology","tag-biological-sciences","tag-brain","tag-chemistry","tag-michelson-center-for-convergent-bioscience","tag-quantitative-and-computational-biology","tag-research"],"acf":[],"yoast_head":"<!-- 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Narcan engage a key brain receptor, opening new avenues to safer drugs\" \/>\n<meta property=\"og:url\" content=\"https:\/\/dornsife.usc.edu\/news\/stories\/mu-opioid-receptor-structural-change-revealed-by-cryo-em\/\" \/>\n<meta property=\"og:site_name\" content=\"USC Dornsife News\" \/>\n<meta property=\"article:publisher\" content=\"https:\/\/www.facebook.com\/uscdornsife\" \/>\n<meta property=\"article:published_time\" content=\"2025-11-05T16:00:00+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2026-03-05T00:56:02+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/dornsife.usc.edu\/news\/wp-content\/uploads\/sites\/7\/2025\/11\/gati-mu-opioid-receptor-top.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"2000\" \/>\n\t<meta property=\"og:image:height\" content=\"1150\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Darrin Joy\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" 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