{"id":4733,"date":"2019-06-14T16:33:38","date_gmt":"2019-06-14T15:33:38","guid":{"rendered":"https:\/\/www.blopig.com\/blog\/?p=4733"},"modified":"2019-06-14T16:33:41","modified_gmt":"2019-06-14T15:33:41","slug":"modelling-conformational-flexibility-of-kinases-in-inactive-states","status":"publish","type":"post","link":"https:\/\/www.blopig.com\/blog\/2019\/06\/modelling-conformational-flexibility-of-kinases-in-inactive-states\/","title":{"rendered":"Modelling Conformational Flexibility of Kinases in Inactive States"},"content":{"rendered":"\n

I would like to shamelessly advertise my master thesis project<\/a> which just got published in Proteins<\/em>. Keep on reading if you are interested in kinases and\/or systematic modelling of protein families.<\/p>\n\n\n\n\n\n\n\n

Protein kinases are\nplayers in intracellular signalling and popular drug targets of the\npharmaceutical industry. Active sites of protein kinases are highly conserved\nand therefore difficult to target selectively. Identifying selectivity-determining\nfeatures is fairly difficult and our methodology may help by systematic modelling\nof kinase conformations in the so called \u2018DFG-out\u2019 state. The DFG motif (one-letter\ncode for aspartic acid, phenylalanine, glycine) is highly conserved amongst\nkinases and its orientation is crucial for the kinase\u2019s catalytic activity (\u2018DFG-out\u2019\nis generally inactive). Other kinase features have distinct conformations as\nwell, namely the activation loop (A-loop) that binds the kinase\u2019s protein substrate,\nthe P-loop which stacks above the nucleotide substrate and the \u03b1C-helix which\ncontains an important glutamic acid.<\/p>\n\n\n\n

You might ask yourself\nnow, why \u2018DFG-out\u2019 and not \u2018DFG-in\u2019? The \u2018DFG-out\u2019 state is inactive and thus structurally\nless conserved. People suspected to find more selectivity-determining features\nthan in the structurally conserved active state, but this could not be shown yet.\nThe actual reason is therefore the potential for new intellectual property (IP)\nas \u2018DFG-in\u2019 inhibitors had been the focus of pharmaceutical research previously.\nThis is also reflected in the number of PDB structures; compared to \u2018DFG-in\u2019\nstructures, \u2018DFG-out\u2019 structures are largely underrepresented (also, \u2018DFG-in\u2019\nstates are easier to crystallise). <\/p>\n\n\n\n

Our approach uses distinct classes of the three flexible kinase features (see Figure 1) and systematically combines them to generate 18 different homology models for each kinase (in the \u2018DFG-out\u2019 state). To achieve this, we classified all human kinases in the PDB and selected template structures that were in the \u2018DFG-out\u2019 state and also contained a certain flexible feature in a certain class. We then structurally aligned them and stitched together 18 chimeric templates, each representing a different combination of A-loop, P-loop and \u03b1C-helix. Using this approach generated model ensembles for over 95% of the human kinome.<\/p>\n\n\n\n

\"\"
Figure 1: Distinct classes of flexible kinase features.<\/figcaption><\/figure>\n\n\n\n

Keep on reading the article for more technical details and our analysis of the generated homology models:<\/p>\n\n\n\n

\n\nSchwarz et al.<\/em> 2019: Modelling conformational flexibility of kinases in inactive states<\/a>.\n\n<\/p>\n\n\n\n

<\/p>\n","protected":false},"excerpt":{"rendered":"

I would like to shamelessly advertise my master thesis project which just got published in Proteins. Keep on reading if you are interested in kinases and\/or systematic modelling of protein families.<\/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":[228,48],"tags":[],"ppma_author":[539],"class_list":["post-4733","post","type-post","status-publish","format-standard","hentry","category-protein-structure","category-publication"],"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\/4733","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=4733"}],"version-history":[{"count":1,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/4733\/revisions"}],"predecessor-version":[{"id":4735,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/4733\/revisions\/4735"}],"wp:attachment":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/media?parent=4733"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/categories?post=4733"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/tags?post=4733"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/ppma_author?post=4733"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}