{"id":564715,"date":"2023-03-17T00:09:06","date_gmt":"2023-03-16T21:09:06","guid":{"rendered":"https:\/\/en.buradabiliyorum.com\/protein-engineers-navigate-toward-more-targeted-therapeutics\/"},"modified":"2023-03-17T00:09:06","modified_gmt":"2023-03-16T21:09:06","slug":"protein-engineers-navigate-toward-more-targeted-therapeutics","status":"publish","type":"post","link":"https:\/\/buradabiliyorum.com\/en\/protein-engineers-navigate-toward-more-targeted-therapeutics\/","title":{"rendered":"#Protein engineers navigate toward more targeted therapeutics"},"content":{"rendered":"<div id=\"ez-toc-container\" class=\"ez-toc-v2_0_84 counter-hierarchy ez-toc-counter ez-toc-custom ez-toc-container-direction\">\n<p class=\"ez-toc-title\" style=\"cursor:inherit\">Table of Contents<\/p>\n<label for=\"ez-toc-cssicon-toggle-item-6a28bb50f15fb\" class=\"ez-toc-cssicon-toggle-label\"><span class=\"\"><span class=\"eztoc-hide\" style=\"display:none;\">Toggle<\/span><span class=\"ez-toc-icon-toggle-span\"><svg style=\"fill: #dd3333;color:#dd3333\" xmlns=\"http:\/\/www.w3.org\/2000\/svg\" class=\"list-377408\" width=\"20px\" height=\"20px\" viewBox=\"0 0 24 24\" fill=\"none\"><path d=\"M6 6H4v2h2V6zm14 0H8v2h12V6zM4 11h2v2H4v-2zm16 0H8v2h12v-2zM4 16h2v2H4v-2zm16 0H8v2h12v-2z\" fill=\"currentColor\"><\/path><\/svg><svg style=\"fill: #dd3333;color:#dd3333\" class=\"arrow-unsorted-368013\" xmlns=\"http:\/\/www.w3.org\/2000\/svg\" width=\"10px\" height=\"10px\" viewBox=\"0 0 24 24\" version=\"1.2\" baseProfile=\"tiny\"><path d=\"M18.2 9.3l-6.2-6.3-6.2 6.3c-.2.2-.3.4-.3.7s.1.5.3.7c.2.2.4.3.7.3h11c.3 0 .5-.1.7-.3.2-.2.3-.5.3-.7s-.1-.5-.3-.7zM5.8 14.7l6.2 6.3 6.2-6.3c.2-.2.3-.5.3-.7s-.1-.5-.3-.7c-.2-.2-.4-.3-.7-.3h-11c-.3 0-.5.1-.7.3-.2.2-.3.5-.3.7s.1.5.3.7z\"\/><\/svg><\/span><\/span><\/label><input type=\"checkbox\"  id=\"ez-toc-cssicon-toggle-item-6a28bb50f15fb\" checked aria-label=\"Toggle\" \/><nav><ul class='ez-toc-list ez-toc-list-level-1 ' ><li class='ez-toc-page-1 ez-toc-heading-level-1'><a class=\"ez-toc-link ez-toc-heading-1\" href=\"https:\/\/buradabiliyorum.com\/en\/protein-engineers-navigate-toward-more-targeted-therapeutics\/#%E2%80%9CProtein_engineers_navigate_toward_more_targeted_therapeutics%E2%80%9D\" >&#8220;Protein engineers navigate toward more targeted therapeutics&#8221;<\/a><\/li><\/ul><\/nav><\/div>\n<h1><span class=\"ez-toc-section\" id=\"%E2%80%9CProtein_engineers_navigate_toward_more_targeted_therapeutics%E2%80%9D\"><\/span>&#8220;Protein engineers navigate toward more targeted therapeutics&#8221;<span class=\"ez-toc-section-end\"><\/span><\/h1>\n<div>\n<div class=\"article-gallery lightGallery\">\n<div data-thumb=\"https:\/\/scx1.b-cdn.net\/csz\/news\/tmb\/2023\/protein-engineers-navi.jpg\" data-src=\"https:\/\/scx2.b-cdn.net\/gfx\/news\/2023\/protein-engineers-navi.jpg\" data-sub-html=\"Agonist- and cytoplasmic effector-binding proteins drive conformational changes in ICL3. a, Schematic of the \u03b22AR ICL3 FRET sensor. Membrane extracts of cells expressing \u03b22AR(L258Azi\/Y350Azi\/\u2206351\u2013413) were labeled with Alkyne-AZDye488 and Alkyne-AZDye546 to generate the sensor. b, FRET efficiency of untreated sensor (buffer), sensor treated with isoproterenol (100\u2009\u00b5M), sensor treated with isoproterenol and nanobody Nb6B9 (500 nM) or sensor treated with isoproterenol and 10\u2009\u00b5M G&lt;sub&gt;s&lt;\/sub&gt; peptide (10\u2009\u00b5M). FRET efficiency is defined as 1\u2009\u2212\u2009&lt;sub&gt;\u03c4FRET\/\u03c4donor&lt;\/sub&gt;, where &lt;sub&gt;\u03c4FRET&lt;\/sub&gt; is the average lifetime of the FRET sensor (Extended Data Fig. 4p, gray bars) and &lt;sub&gt;\u03c4donor&lt;\/sub&gt; is the average lifetime of an AZDye488-only-labeled control sample (Extended Data Fig. 4p, white bars). Box edges delineate the 1st and 3rd quartiles of the data, the center line represents the median, whiskers represent the furthest points within 1.5\u00d7 the interquartile rangean and points represent five independent experiments. One-way ANOVA followed by Tukey\u2019s post hoc significance test; ***P\u2009is less than\u20090.001 (F\u2009=\u200915.2, P\u2009=\u20096\u2009\u00d7\u200910&lt;sup&gt;\u22126&lt;\/sup&gt;, 16 d.f.). c, Proposed sensor readout of ICL3 conformational equilibrium. Left, in the receptor\u2019s inactive state, the donor and acceptor probes are further apart, resulting in low FRET. Center, agonist (isoproterenol) binding increases probe proximity, thereby increasing FRET efficiency (intermediate). Right, formation of agonist\u2013receptor\u2013effector (with Nb6B9 or G&lt;sub&gt;s&lt;\/sub&gt; peptide) complex displaces ICL3 from the intracellular cavity, extending the distance between donor and acceptor probes and quenching the FRET readout. Credit: &lt;i&gt;Nature&lt;\/i&gt; (2023). DOI: 10.1038\/s41586-023-05789-z\">\n<figure class=\"article-img\"><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/scx1.b-cdn.net\/csz\/news\/800a\/2023\/protein-engineers-navi.jpg\" alt=\"Protein engineers navigate toward more targeted therapeutics\" title=\"Agonist- and cytoplasmic effector-binding proteins drive conformational changes in ICL3. a, Schematic of the \u03b22AR ICL3 FRET sensor. Membrane extracts of cells expressing \u03b22AR(L258Azi\/Y350Azi\/\u2206351\u2013413) were labeled with Alkyne-AZDye488 and Alkyne-AZDye546 to generate the sensor. b, FRET efficiency of untreated sensor (buffer), sensor treated with isoproterenol (100\u2009\u00b5M), sensor treated with isoproterenol and nanobody Nb6B9 (500 nM) or sensor treated with isoproterenol and 10\u2009\u00b5M G s  peptide (10\u2009\u00b5M). FRET efficiency is defined as 1\u2009\u2212\u2009 \u03c4FRET\/\u03c4donor , where  \u03c4FRET  is the average lifetime of the FRET sensor (Extended Data Fig. 4p, gray bars) and  \u03c4donor  is the average lifetime of an AZDye488-only-labeled control sample (Extended Data Fig. 4p, white bars). Box edges delineate the 1st and 3rd quartiles of the data, the center line represents the median, whiskers represent the furthest points within 1.5\u00d7 the interquartile rangean and points represent five independent experiments. One-way ANOVA followed by Tukey\u2019s post hoc significance test; ***P\u2009is less than\u20090.001 (F\u2009=\u200915.2, P\u2009=\u20096\u2009\u00d7\u200910 \u22126 , 16 d.f.). c, Proposed sensor readout of ICL3 conformational equilibrium. Left, in the receptor\u2019s inactive state, the donor and acceptor probes are further apart, resulting in low FRET. Center, agonist (isoproterenol) binding increases probe proximity, thereby increasing FRET efficiency (intermediate). Right, formation of agonist\u2013receptor\u2013effector (with Nb6B9 or G s  peptide) complex displaces ICL3 from the intracellular cavity, extending the distance between donor and acceptor probes and quenching the FRET readout. Credit:  Nature  (2023). DOI: 10.1038\/s41586-023-05789-z\" width=\"800\" height=\"530\"\/><figcaption class=\"text-darken text-low-up text-truncate-js text-truncate mt-3\">\n                Agonist- and cytoplasmic effector-binding proteins drive conformational changes in ICL3. a, Schematic of the \u03b22AR ICL3 FRET sensor. Membrane extracts of cells expressing \u03b22AR(L258Azi\/Y350Azi\/\u2206351\u2013413) were labeled with Alkyne-AZDye488 and Alkyne-AZDye546 to generate the sensor. b, FRET efficiency of untreated sensor (buffer), sensor treated with isoproterenol (100\u2009\u00b5M), sensor treated with isoproterenol and nanobody Nb6B9 (500 nM) or sensor treated with isoproterenol and 10\u2009\u00b5M G<sub>s<\/sub> peptide (10\u2009\u00b5M). FRET efficiency is defined as 1\u2009\u2212\u2009<sub>\u03c4FRET\/\u03c4donor<\/sub>, where <sub>\u03c4FRET<\/sub> is the average lifetime of the FRET sensor (Extended Data Fig. 4p, gray bars) and <sub>\u03c4donor<\/sub> is the average lifetime of an AZDye488-only-labeled control sample (Extended Data Fig. 4p, white bars). Box edges delineate the 1st and 3rd quartiles of the data, the center line represents the <a href=\"https:\/\/buradabiliyorum.com\/en\/category\/social-mediaa\/\" data-internallinksmanager029f6b8e52c=\"1\" title=\"Social Media\" target=\"_blank\" rel=\"noopener\">media<\/a>n, whiskers represent the furthest points within 1.5\u00d7 the interquartile rangean and points represent five independent experiments. One-way ANOVA followed by Tukey\u2019s post hoc significance test; ***P\u2009is less than\u20090.001 (F\u2009=\u200915.2, P\u2009=\u20096\u2009\u00d7\u200910<sup>\u22126<\/sup>, 16 d.f.). c, Proposed sensor readout of ICL3 conformational equilibrium. Left, in the receptor\u2019s inactive state, the donor and acceptor probes are further apart, resulting in low FRET. Center, agonist (isoproterenol) binding increases probe proximity, thereby increasing FRET efficiency (intermediate). Right, formation of agonist\u2013receptor\u2013effector (with Nb6B9 or G<sub>s<\/sub> peptide) complex displaces ICL3 from the intracellular cavity, extending the distance between donor and acceptor probes and quenching the FRET readout. Credit: <i>Nature<\/i> (2023). DOI: 10.1038\/s41586-023-05789-z<br \/>\n            <\/figcaption><\/figure>\n<\/div>\n<\/div>\n<p>More than a third of FDA-<a href=\"https:\/\/buradabiliyorum.com\/en\/category\/download-scripts-themes-apps\/\" data-internallinksmanager029f6b8e52c=\"9\" title=\"Download Scripts &amp; Themes &amp; Apps\" target=\"_blank\" rel=\"noopener\">app<\/a>roved drugs work by targeting a G protein-coupled receptor, or GPCR. The human body has more than 800 types of GPCRs that provide cells with information about the external environment to calibrate responses. Drugs that either block or activate GPCRs are used to treat a wide range of diseases including hypertension, pain and inflammation. Most drugs bind to the outside of the receptor, but this can result in adverse side effects since receptors often resemble one another.<\/p>\n<p>In a new study published in <i>Nature<\/i>, Sivaraj Sivaramakrishnan, a professor in the University of Minnesota College of Biological <a href=\"https:\/\/buradabiliyorum.com\/en\/category\/sciencee\/\" data-internallinksmanager029f6b8e52c=\"5\" title=\"Science\" target=\"_blank\" rel=\"noopener\">Science<\/a>s, along with graduate student Fred Sadler and co-authors Michael Ritt and Yatharth Sharma, uncovered the role of the third intracellular loop in the GPCR&#8217;s signaling mechanism, suggesting the possibility of a more targeted approach to drug discovery and a paradigm shift for new therapeutics.<\/p>\n<p>&#8220;Typical GPCR drugs act as on or off switches for cellular signaling outcomes,&#8221; said Sivaramakrishnan. &#8220;Drugs that leverage the loop effectively can act as signaling dimmer switches to more precisely control drug responses.&#8221;<\/p>\n<p>The authors developed new biochemical and biophysical tools, combined with computational measurements by collaborators Ning Ma and Nagarajan Vaidehi at the City of Hope Cancer Center. They tracked how the third intracellular loop changes in shape, or conformation, through the receptor signaling process. In a breakthrough for the field, their data show that the loop acts as a kind of gate to ensure that receptors activate the correct type of G protein signaling at the right intensity.<\/p>\n<p>&#8220;A key advantage of this loop is that it is highly unique, even among closely related receptors, making it an outstanding drug target,&#8221; said Sadler. &#8220;Developing drugs through this newly discovered mechanism would allow for far more targeted therapeutics.&#8221;<\/p>\n<div class=\"article-main__more p-4\">\n                                                                                        <strong>More information:<\/strong><br \/>\n                                                Fredrik Sadler et al, Autoregulation of GPCR signalling through the third intracellular loop, <i>Nature<\/i> (2023).  <a rel=\"nofollow noopener\" target=\"_blank\" data-doi=\"1\" href=\"https:\/\/dx.doi.org\/10.1038\/s41586-023-05789-z\">DOI: 10.1038\/s41586-023-05789-z<\/a><\/p><\/div>\n<div class=\"d-inline-block text-medium mt-4\">\n<p>                                                    Provided by<br \/>\n                                                                                                            University of Minnesota<br \/>\n                                                                                                                <a rel=\"nofollow noopener\" target=\"_blank\" class=\"icon_open\" href=\"http:\/\/www.umn.edu\/\"><br \/>\n                                                            <svg><use href=\"https:\/\/phys.b-cdn.net\/tmpl\/v6\/img\/svg\/sprite.svg#icon_open\" x=\"0\" y=\"0\"\/><\/svg><\/a><\/p><\/div>\n<p>                                        <!-- print only --><\/p>\n<div class=\"d-none d-print-block\">\n<p>                                                <strong>Citation<\/strong>:<br \/>\n                                                Protein engineers navigate toward more targeted therapeutics (2023, March 16)<br \/>\n                                                retrieved 16 March 2023<br \/>\n                                                from https:\/\/phys.org\/<a href=\"https:\/\/buradabiliyorum.com\/en\/category\/news\/\" data-internallinksmanager029f6b8e52c=\"2\" title=\"News\" target=\"_blank\" rel=\"noopener\">news<\/a>\/2023-03-protein-therapeutics.html<\/p>\n<p>                                             This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no<br \/>\n                                             part may be reproduced without the written permission. The content is provided for information purposes only.<\/p><\/div>\n<\/p><\/div>\n<p><script id=\"facebook-jssdk\" async=\"\" src=\"https:\/\/connect.facebook.net\/en_US\/sdk.js\"><\/script><\/p>\n<blockquote><p><strong><span style=\"color: #ff6600;\">If you liked the article, do not forget to share it with your friends. Follow us on\u00a0<span style=\"color: #ff0000;\"><a style=\"color: #ff0000;\" href=\"https:\/\/news.google.com\/publications\/CAAqBwgKMLG0nwswvr63Aw\" target=\"_blank\" rel=\"nofollow noopener noreferrer\">Google News<\/a><\/span>\u00a0too, click on the star and choose us from your favorites.<\/span><\/strong><\/p><\/blockquote>\n<blockquote>\n<p style=\"text-align: center;\">For forums sites go to <span style=\"color: #ff9900;\"><a style=\"color: #ff9900;\" href=\"https:\/\/forum.buradabiliyorum.com\/\" target=\"_blank\" rel=\"noopener\">Forum.BuradaBiliyorum.Com<\/a><\/span><\/strong>\n<\/p><\/blockquote>\n<blockquote>\n<p style=\"text-align: center;\"><strong>If you want to read more Like this articles, you can visit our <span style=\"color: #ff9900;\"><a style=\"color: #ff9900;\" href=\"https:\/\/en.buradabiliyorum.com\/science\/\" target=\"_blank\" rel=\"noopener\">Science category.<\/a><\/span><\/strong><\/p>\n<\/blockquote>\n<p><span style=\"color: black;\"><a style=\"color: #ff9900;\" href=\"https:\/\/phys.org\/news\/2023-03-protein-therapeutics.html\" target=\"_blank\" rel=\"noopener\">Source<\/a><\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>&#8220;Protein engineers navigate toward more targeted therapeutics&#8221; Agonist- and cytoplasmic effector-binding proteins drive conformational changes in ICL3. a, Schematic of the \u03b22AR ICL3 FRET sensor. Membrane extracts of cells expressing \u03b22AR(L258Azi\/Y350Azi\/\u2206351\u2013413) were labeled with Alkyne-AZDye488 and Alkyne-AZDye546 to generate the sensor. b, FRET efficiency of untreated sensor (buffer), sensor treated with isoproterenol (100\u2009\u00b5M), sensor treated&#8230;<\/p>\n","protected":false},"author":1,"featured_media":564716,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"fifu_image_url":"https:\/\/scx2.b-cdn.net\/gfx\/news\/2023\/protein-engineers-navi.jpg","fifu_image_alt":"","footnotes":""},"categories":[16],"tags":[],"class_list":["post-564715","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-sciencee"],"_links":{"self":[{"href":"https:\/\/buradabiliyorum.com\/en\/wp-json\/wp\/v2\/posts\/564715","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/buradabiliyorum.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/buradabiliyorum.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/buradabiliyorum.com\/en\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/buradabiliyorum.com\/en\/wp-json\/wp\/v2\/comments?post=564715"}],"version-history":[{"count":0,"href":"https:\/\/buradabiliyorum.com\/en\/wp-json\/wp\/v2\/posts\/564715\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/buradabiliyorum.com\/en\/wp-json\/wp\/v2\/media\/564716"}],"wp:attachment":[{"href":"https:\/\/buradabiliyorum.com\/en\/wp-json\/wp\/v2\/media?parent=564715"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/buradabiliyorum.com\/en\/wp-json\/wp\/v2\/categories?post=564715"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/buradabiliyorum.com\/en\/wp-json\/wp\/v2\/tags?post=564715"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}