Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex
The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natur...
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| Veröffentlicht in: | Acta crystallographica. Section D, Biological crystallography. Biological crystallography., 2014-10, Vol.70 (10), p.2765-2774 |
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| container_title | Acta crystallographica. Section D, Biological crystallography. |
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| creator | Žáková, Lenka Kletvíková, Emília Lepšík, Martin Collinsová, Michaela Watson, Christopher J. Turkenburg, Johan P. Jiráček, Jiří Brzozowski, Andrzej M. |
| description | The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]‐insulin and [GlyB26]‐insulin attain a B26‐turn‐like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26‐turn‐like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B‐chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms. |
| doi_str_mv | 10.1107/S1399004714017775 |
| format | Article |
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Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]‐insulin and [GlyB26]‐insulin attain a B26‐turn‐like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26‐turn‐like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B‐chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.</description><identifier>ISSN: 1399-0047</identifier><identifier>ISSN: 0907-4449</identifier><identifier>EISSN: 1399-0047</identifier><identifier>DOI: 10.1107/S1399004714017775</identifier><identifier>PMID: 25286859</identifier><language>eng</language><publisher>5 Abbey Square, Chester, Cheshire CH1 2HU, England: International Union of Crystallography</publisher><subject>active conformation ; Amino Acid Substitution ; Animals ; Cells, Cultured ; complex ; COMPLEXES ; CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY ; Crystallography, X-Ray ; Fibroblasts - metabolism ; Humans ; Hyperglycemia ; Insulin ; Insulin - analogs & derivatives ; Insulin - chemistry ; Insulin - genetics ; Insulin - metabolism ; insulin receptor ; INTERACTIONS ; INTERFACES ; isothermal titration microcalorimetry ; Lymphocytes - metabolism ; Male ; Mice ; Mice, Knockout ; Models, Molecular ; MODIFICATIONS ; molecular dynamics ; MOLECULAR DYNAMICS METHOD ; Mutation ; ORIGIN ; Phenylalanine ; Protein Conformation ; Rats, Wistar ; Receptor, Insulin - chemistry ; Receptor, Insulin - metabolism ; RECEPTORS ; Research Papers ; SPECIFICITY ; SPECTRA</subject><ispartof>Acta crystallographica. Section D, Biological crystallography., 2014-10, Vol.70 (10), p.2765-2774</ispartof><rights>Žáková et al. 2014</rights><rights>áková et al. 2014</rights><rights>Žáková et al. 2014 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5430-47b14f86dc4e22be2bf48aad25c052f696488de14e98ea3685337004ff183e863</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1107%2FS1399004714017775$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1107%2FS1399004714017775$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25286859$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/22347759$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Žáková, Lenka</creatorcontrib><creatorcontrib>Kletvíková, Emília</creatorcontrib><creatorcontrib>Lepšík, Martin</creatorcontrib><creatorcontrib>Collinsová, Michaela</creatorcontrib><creatorcontrib>Watson, Christopher J.</creatorcontrib><creatorcontrib>Turkenburg, Johan P.</creatorcontrib><creatorcontrib>Jiráček, Jiří</creatorcontrib><creatorcontrib>Brzozowski, Andrzej M.</creatorcontrib><title>Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex</title><title>Acta crystallographica. Section D, Biological crystallography.</title><addtitle>Acta Crystallographica D</addtitle><description>The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]‐insulin and [GlyB26]‐insulin attain a B26‐turn‐like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26‐turn‐like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B‐chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.</description><subject>active conformation</subject><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Cells, Cultured</subject><subject>complex</subject><subject>COMPLEXES</subject><subject>CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY</subject><subject>Crystallography, X-Ray</subject><subject>Fibroblasts - metabolism</subject><subject>Humans</subject><subject>Hyperglycemia</subject><subject>Insulin</subject><subject>Insulin - analogs & derivatives</subject><subject>Insulin - chemistry</subject><subject>Insulin - genetics</subject><subject>Insulin - metabolism</subject><subject>insulin receptor</subject><subject>INTERACTIONS</subject><subject>INTERFACES</subject><subject>isothermal titration microcalorimetry</subject><subject>Lymphocytes - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Models, Molecular</subject><subject>MODIFICATIONS</subject><subject>molecular dynamics</subject><subject>MOLECULAR DYNAMICS METHOD</subject><subject>Mutation</subject><subject>ORIGIN</subject><subject>Phenylalanine</subject><subject>Protein Conformation</subject><subject>Rats, Wistar</subject><subject>Receptor, Insulin - chemistry</subject><subject>Receptor, Insulin - metabolism</subject><subject>RECEPTORS</subject><subject>Research Papers</subject><subject>SPECIFICITY</subject><subject>SPECTRA</subject><issn>1399-0047</issn><issn>0907-4449</issn><issn>1399-0047</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNqFkUtv1DAUhSMEoqXwA9ggS6wDfsV2NkhlBlpEBUKAeGwsj3PTcUnsqe2Uzr_HQ2AoYsHKV_Z3jnzOraqHBD8hBMun7wlrW4y5JBwTKWVzqzrcXdW7u9s35oPqXkoXGGNKmbxbHdCGKqGa9rDank6j8cj5NA3OI-PNEM4nSGgMnesddMhklNeAnlOBksuAIlyBGZBB6xDH4AHZ4PsymuyCL2jhXUKT7yCDzcXA-Z8GESxscoiFHzcDXN-v7vRmSPDg13lUfXz54sPitD57e_JqcXxW24YzXHO5IrxXorMcKF0BXfVcGdPRxuKG9qIVXKkOCIdWgWElFWOyZO57ohgowY6qZ7PvZlqN0FnwOZpBb6IbTdzqYJz--8W7tT4PV5oTpTBpisHj2SCk7HSypQS7LqF9iadLobwU3_6hNjFclgKzvghTLHUmTQRusRBE7rzITNkYUorQ7_9BsN7tVP-z06J5dDPAXvF7iQVoZ-C7G2D7f0d9_GVJl18bxnHR1rPWpQzXe62J37SQrLCf3pzoxTu2lMvXUn9mPwB4eLyF</recordid><startdate>201410</startdate><enddate>201410</enddate><creator>Žáková, Lenka</creator><creator>Kletvíková, Emília</creator><creator>Lepšík, Martin</creator><creator>Collinsová, Michaela</creator><creator>Watson, Christopher J.</creator><creator>Turkenburg, Johan P.</creator><creator>Jiráček, Jiří</creator><creator>Brzozowski, Andrzej M.</creator><general>International Union of Crystallography</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>24P</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7SP</scope><scope>7SR</scope><scope>7TK</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>H8D</scope><scope>JG9</scope><scope>L7M</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>201410</creationdate><title>Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex</title><author>Žáková, Lenka ; 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Section D, Biological crystallography.</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Žáková, Lenka</au><au>Kletvíková, Emília</au><au>Lepšík, Martin</au><au>Collinsová, Michaela</au><au>Watson, Christopher J.</au><au>Turkenburg, Johan P.</au><au>Jiráček, Jiří</au><au>Brzozowski, Andrzej M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex</atitle><jtitle>Acta crystallographica. Section D, Biological crystallography.</jtitle><addtitle>Acta Crystallographica D</addtitle><date>2014-10</date><risdate>2014</risdate><volume>70</volume><issue>10</issue><spage>2765</spage><epage>2774</epage><pages>2765-2774</pages><issn>1399-0047</issn><issn>0907-4449</issn><eissn>1399-0047</eissn><abstract>The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]‐insulin and [GlyB26]‐insulin attain a B26‐turn‐like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26‐turn‐like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B‐chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.</abstract><cop>5 Abbey Square, Chester, Cheshire CH1 2HU, England</cop><pub>International Union of Crystallography</pub><pmid>25286859</pmid><doi>10.1107/S1399004714017775</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Acta crystallographica. Section D, Biological crystallography., 2014-10, Vol.70 (10), p.2765-2774 |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Alma/SFX Local Collection |
| subjects | active conformation Amino Acid Substitution Animals Cells, Cultured complex COMPLEXES CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY Crystallography, X-Ray Fibroblasts - metabolism Humans Hyperglycemia Insulin Insulin - analogs & derivatives Insulin - chemistry Insulin - genetics Insulin - metabolism insulin receptor INTERACTIONS INTERFACES isothermal titration microcalorimetry Lymphocytes - metabolism Male Mice Mice, Knockout Models, Molecular MODIFICATIONS molecular dynamics MOLECULAR DYNAMICS METHOD Mutation ORIGIN Phenylalanine Protein Conformation Rats, Wistar Receptor, Insulin - chemistry Receptor, Insulin - metabolism RECEPTORS Research Papers SPECIFICITY SPECTRA |
| title | Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex |
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