{"id":6899,"date":"2021-06-11T18:22:54","date_gmt":"2021-06-11T17:22:54","guid":{"rendered":"https:\/\/www.blopig.com\/blog\/?p=6899"},"modified":"2021-06-16T12:26:07","modified_gmt":"2021-06-16T11:26:07","slug":"the-smallest-allosteric-system","status":"publish","type":"post","link":"https:\/\/www.blopig.com\/blog\/2021\/06\/the-smallest-allosteric-system\/","title":{"rendered":"The Smallest Allosteric System"},"content":{"rendered":"\n

Allostery is still a badly understood but very general mechanism in the protein world. In principle, an allosteric event occurs when a ligand (small or big) binds to a certain site of a protein and something (activity or function) changes at a different, distant site. A well-known example would be G-protein-coupled receptors that transport such an allosteric signal even across a membrane. But it does not have to be that far apart. As part of the Protein Folding and Dynamics series<\/a>, I have recently watched a talk by Peter Hamm (Zurich) who presented work on an allosteric system that I thought was very interesting because it was small and most importantly, controllable.<\/p>\n\n\n\n

PDZ domains are peptide-binding domains, often part of multi-domain proteins. For the work presented the researchers used the PDZ3 domain which is a bit special and has an additional (third) C-terminal \u03b1<\/em>-helix (\u03b1<\/em>3-helix) which is packing to the other side of the binding pocket. Previous work (Petit et al.<\/em> 2009<\/a>) had shown that removal of the \u03b1<\/em>3-helix had changed ligand affinity but not PDZ structure, major changes were of an entropic nature instead. Peter Hamm\u2019s group linked an azobenzene-derived photoswitch to that \u03b1<\/em>3-helix; in its cis<\/em> configuration stabilizing the \u03b1<\/em>3-helix and destabilising in trans<\/em> (see Figure 1).<\/p>\n\n\n\n

\"\"<\/a>
Figure 1: PDZ3 domain (purple) and photoswitch (red) have different affinities for the peptide ligand (green), depending on the photoswitch’s isomerisation state (and temperature). From Bozovic, O., Jankovic, B. & Hamm, P. Sensing the allosteric force. Nat Commun<\/em> 11, <\/strong>5841 (2020). https:\/\/doi.org\/10.1038\/s41467-020-19689-7 <\/figcaption><\/figure>\n\n\n\n\n\n\n\n

What they found was that by switching from trans to cis, the helix was stabilized and the binding affinity for the ligand increased (up to 120-fold, temperature-dependent) at that distant site (hence an allosteric event). This allosteric communication also worked in the other direction as the rate of cis<\/em>-to-trans<\/em> isomerisation increased when the ligand was bound (compared to the native isomerisation rate without ligand). This combination of a small peptide-binding domain and a photoswitch constitutes a very small allosteric system (the smallest known today?) which states can be controlled by light and ligands. The size and controllability of this systems might open up more in-depth studies on how a (or at least this) allosteric signal is transmitted inside a protein.<\/p>\n\n\n\n

They further determined binding enthalpies, the difference in driving force for cis<\/em>-to-trans<\/em> isomerisation and resulting from that, a force that is transmitted through the allosteric events and therefore termed \u2018allosteric force\u2019. For more details on their theoretical considerations for this as well as the experiments have a look at their paper: Sensing the allosteric force<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"

Allostery is still a badly understood but very general mechanism in the protein world. In principle, an allosteric event occurs when a ligand (small or big) binds to a certain site of a protein and something (activity or function) changes at a different, distant site. A well-known example would be G-protein-coupled receptors that transport such […]<\/p>\n","protected":false},"author":55,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"nf_dc_page":"","wikipediapreview_detectlinks":true,"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"ngg_post_thumbnail":0,"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[138,228,202],"tags":[163],"ppma_author":[539],"class_list":["post-6899","post","type-post","status-publish","format-standard","hentry","category-journal-club","category-protein-structure","category-proteins","tag-allostery"],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"authors":[{"term_id":539,"user_id":55,"is_guest":0,"slug":"dominik","display_name":"Dominik","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/56bd12e029ec48ca4480b0927066663d35abe9d040c80e2ed0ace3f60b41419f?s=96&d=mm&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/6899","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/users\/55"}],"replies":[{"embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/comments?post=6899"}],"version-history":[{"count":4,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/6899\/revisions"}],"predecessor-version":[{"id":6971,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/6899\/revisions\/6971"}],"wp:attachment":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/media?parent=6899"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/categories?post=6899"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/tags?post=6899"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/ppma_author?post=6899"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}