A new regulatory switch in a JAK protein kinase
Members of the JAK family of protein kinases mediate signal transduction from cytokine receptors to transcription factor activation. Over‐stimulation of these pathways is causative in immune disorders like rheumatoid arthritis, psoriasis, lupus, and Crohn's disease. A search for selective inhib...
Gespeichert in:
| Veröffentlicht in: | Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2011-02, Vol.79 (2), p.393-401 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 401 |
|---|---|
| container_issue | 2 |
| container_start_page | 393 |
| container_title | Proteins, structure, function, and bioinformatics |
| container_volume | 79 |
| creator | Tsui, Vickie Gibbons, Paul Ultsch, Mark Mortara, Kyle Chang, Christine Blair, Wade Pulk, Rebecca Stanley, Mark Starovasnik, Melissa Williams, David Lamers, Maria Leonard, Phillip Magnuson, Steven Liang, Jun Eigenbrot, Charles |
| description | Members of the JAK family of protein kinases mediate signal transduction from cytokine receptors to transcription factor activation. Over‐stimulation of these pathways is causative in immune disorders like rheumatoid arthritis, psoriasis, lupus, and Crohn's disease. A search for selective inhibitors of a JAK kinase has led to our characterization of a previously unknown kinase conformation arising from presentation of Tyr962 of TYK2 to an inhibitory small molecule via an H‐bonding interaction. A small minority of protein kinase domains has a Tyrosine residue in this position within the αC‐β4 loop, and it is the only amino acid commonly seen here with H‐bonding potential. These discoveries will aid design of inhibitors that discriminate among the JAK family and more widely among protein kinases. Proteins 2011. © 2010 Wiley‐Liss, Inc. |
| doi_str_mv | 10.1002/prot.22889 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_822710390</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3278831381</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4279-a182624367f459fc7dc3f52be5ec61e4c2b0d347199d2fbedf67f62a0f2511063</originalsourceid><addsrcrecordid>eNp90EFP2zAUB3BrAo3CduEDoEgcNiGFvvcc2_GxqjYGlHVCTDtabuJsgTQBO1Hpt59LgQMHTtaTfu__5D9jhwinCEDje9_1p0R5rj-wEYJWKSDPdtgI8lylXORij-2HcAsAUnP5ke0RIirIYcTGk6R1q8S7v0Nj-86vk7Cq--JfUreJTS4ml8km3cXprm5tcJ_YbmWb4D4_vwfs9_dvN9Mf6Wx-dj6dzNIiI6VTizlJyrhUVSZ0Vaiy4JWghROukOiyghZQ8kyh1iVVC1dWUUqyUJFABMkP2Jdtbjz_MLjQm2UdCtc0tnXdEExOpBC4hii_vitRkNbEJVGkx2_obTf4Nv4jKlRZpghFVCdbVfguBO8qc-_rpfVrg2A2hZtNJeap8IiPniOHxdKVr_Sl4QhwC1Z149bvRJlf1_Obl9B0u1OH3j2-7lh_Z6TiSpg_P88M6Clcza5nRvP_wH2W6Q</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1517447215</pqid></control><display><type>article</type><title>A new regulatory switch in a JAK protein kinase</title><source>MEDLINE</source><source>Wiley Online Library All Journals</source><creator>Tsui, Vickie ; Gibbons, Paul ; Ultsch, Mark ; Mortara, Kyle ; Chang, Christine ; Blair, Wade ; Pulk, Rebecca ; Stanley, Mark ; Starovasnik, Melissa ; Williams, David ; Lamers, Maria ; Leonard, Phillip ; Magnuson, Steven ; Liang, Jun ; Eigenbrot, Charles</creator><creatorcontrib>Tsui, Vickie ; Gibbons, Paul ; Ultsch, Mark ; Mortara, Kyle ; Chang, Christine ; Blair, Wade ; Pulk, Rebecca ; Stanley, Mark ; Starovasnik, Melissa ; Williams, David ; Lamers, Maria ; Leonard, Phillip ; Magnuson, Steven ; Liang, Jun ; Eigenbrot, Charles</creatorcontrib><description>Members of the JAK family of protein kinases mediate signal transduction from cytokine receptors to transcription factor activation. Over‐stimulation of these pathways is causative in immune disorders like rheumatoid arthritis, psoriasis, lupus, and Crohn's disease. A search for selective inhibitors of a JAK kinase has led to our characterization of a previously unknown kinase conformation arising from presentation of Tyr962 of TYK2 to an inhibitory small molecule via an H‐bonding interaction. A small minority of protein kinase domains has a Tyrosine residue in this position within the αC‐β4 loop, and it is the only amino acid commonly seen here with H‐bonding potential. These discoveries will aid design of inhibitors that discriminate among the JAK family and more widely among protein kinases. Proteins 2011. © 2010 Wiley‐Liss, Inc.</description><identifier>ISSN: 0887-3585</identifier><identifier>EISSN: 1097-0134</identifier><identifier>DOI: 10.1002/prot.22889</identifier><identifier>PMID: 21117080</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>binding mode ; Catalytic Domain ; crystal structure ; Crystallography, X-Ray ; Drug Design ; Humans ; Isoquinolines - chemistry ; Models, Molecular ; Mutation ; Protein Binding ; Protein Kinase Inhibitors - chemistry ; Protein Structure, Tertiary ; Quinolines - chemistry ; Recombinant Proteins - antagonists & inhibitors ; Recombinant Proteins - chemistry ; selectivity ; small molecule inhibitor ; Thiophenes - chemistry ; TYK2 ; TYK2 Kinase - antagonists & inhibitors ; TYK2 Kinase - chemistry</subject><ispartof>Proteins, structure, function, and bioinformatics, 2011-02, Vol.79 (2), p.393-401</ispartof><rights>Copyright © 2010 Wiley‐Liss, Inc.</rights><rights>2010 Wiley-Liss, Inc.</rights><rights>Copyright © 2010 Wiley-Liss, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4279-a182624367f459fc7dc3f52be5ec61e4c2b0d347199d2fbedf67f62a0f2511063</citedby><cites>FETCH-LOGICAL-c4279-a182624367f459fc7dc3f52be5ec61e4c2b0d347199d2fbedf67f62a0f2511063</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fprot.22889$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fprot.22889$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21117080$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tsui, Vickie</creatorcontrib><creatorcontrib>Gibbons, Paul</creatorcontrib><creatorcontrib>Ultsch, Mark</creatorcontrib><creatorcontrib>Mortara, Kyle</creatorcontrib><creatorcontrib>Chang, Christine</creatorcontrib><creatorcontrib>Blair, Wade</creatorcontrib><creatorcontrib>Pulk, Rebecca</creatorcontrib><creatorcontrib>Stanley, Mark</creatorcontrib><creatorcontrib>Starovasnik, Melissa</creatorcontrib><creatorcontrib>Williams, David</creatorcontrib><creatorcontrib>Lamers, Maria</creatorcontrib><creatorcontrib>Leonard, Phillip</creatorcontrib><creatorcontrib>Magnuson, Steven</creatorcontrib><creatorcontrib>Liang, Jun</creatorcontrib><creatorcontrib>Eigenbrot, Charles</creatorcontrib><title>A new regulatory switch in a JAK protein kinase</title><title>Proteins, structure, function, and bioinformatics</title><addtitle>Proteins</addtitle><description>Members of the JAK family of protein kinases mediate signal transduction from cytokine receptors to transcription factor activation. Over‐stimulation of these pathways is causative in immune disorders like rheumatoid arthritis, psoriasis, lupus, and Crohn's disease. A search for selective inhibitors of a JAK kinase has led to our characterization of a previously unknown kinase conformation arising from presentation of Tyr962 of TYK2 to an inhibitory small molecule via an H‐bonding interaction. A small minority of protein kinase domains has a Tyrosine residue in this position within the αC‐β4 loop, and it is the only amino acid commonly seen here with H‐bonding potential. These discoveries will aid design of inhibitors that discriminate among the JAK family and more widely among protein kinases. Proteins 2011. © 2010 Wiley‐Liss, Inc.</description><subject>binding mode</subject><subject>Catalytic Domain</subject><subject>crystal structure</subject><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Isoquinolines - chemistry</subject><subject>Models, Molecular</subject><subject>Mutation</subject><subject>Protein Binding</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Structure, Tertiary</subject><subject>Quinolines - chemistry</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Recombinant Proteins - chemistry</subject><subject>selectivity</subject><subject>small molecule inhibitor</subject><subject>Thiophenes - chemistry</subject><subject>TYK2</subject><subject>TYK2 Kinase - antagonists & inhibitors</subject><subject>TYK2 Kinase - chemistry</subject><issn>0887-3585</issn><issn>1097-0134</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90EFP2zAUB3BrAo3CduEDoEgcNiGFvvcc2_GxqjYGlHVCTDtabuJsgTQBO1Hpt59LgQMHTtaTfu__5D9jhwinCEDje9_1p0R5rj-wEYJWKSDPdtgI8lylXORij-2HcAsAUnP5ke0RIirIYcTGk6R1q8S7v0Nj-86vk7Cq--JfUreJTS4ml8km3cXprm5tcJ_YbmWb4D4_vwfs9_dvN9Mf6Wx-dj6dzNIiI6VTizlJyrhUVSZ0Vaiy4JWghROukOiyghZQ8kyh1iVVC1dWUUqyUJFABMkP2Jdtbjz_MLjQm2UdCtc0tnXdEExOpBC4hii_vitRkNbEJVGkx2_obTf4Nv4jKlRZpghFVCdbVfguBO8qc-_rpfVrg2A2hZtNJeap8IiPniOHxdKVr_Sl4QhwC1Z149bvRJlf1_Obl9B0u1OH3j2-7lh_Z6TiSpg_P88M6Clcza5nRvP_wH2W6Q</recordid><startdate>201102</startdate><enddate>201102</enddate><creator>Tsui, Vickie</creator><creator>Gibbons, Paul</creator><creator>Ultsch, Mark</creator><creator>Mortara, Kyle</creator><creator>Chang, Christine</creator><creator>Blair, Wade</creator><creator>Pulk, Rebecca</creator><creator>Stanley, Mark</creator><creator>Starovasnik, Melissa</creator><creator>Williams, David</creator><creator>Lamers, Maria</creator><creator>Leonard, Phillip</creator><creator>Magnuson, Steven</creator><creator>Liang, Jun</creator><creator>Eigenbrot, Charles</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7QL</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201102</creationdate><title>A new regulatory switch in a JAK protein kinase</title><author>Tsui, Vickie ; Gibbons, Paul ; Ultsch, Mark ; Mortara, Kyle ; Chang, Christine ; Blair, Wade ; Pulk, Rebecca ; Stanley, Mark ; Starovasnik, Melissa ; Williams, David ; Lamers, Maria ; Leonard, Phillip ; Magnuson, Steven ; Liang, Jun ; Eigenbrot, Charles</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4279-a182624367f459fc7dc3f52be5ec61e4c2b0d347199d2fbedf67f62a0f2511063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>binding mode</topic><topic>Catalytic Domain</topic><topic>crystal structure</topic><topic>Crystallography, X-Ray</topic><topic>Drug Design</topic><topic>Humans</topic><topic>Isoquinolines - chemistry</topic><topic>Models, Molecular</topic><topic>Mutation</topic><topic>Protein Binding</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Structure, Tertiary</topic><topic>Quinolines - chemistry</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Recombinant Proteins - chemistry</topic><topic>selectivity</topic><topic>small molecule inhibitor</topic><topic>Thiophenes - chemistry</topic><topic>TYK2</topic><topic>TYK2 Kinase - antagonists & inhibitors</topic><topic>TYK2 Kinase - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tsui, Vickie</creatorcontrib><creatorcontrib>Gibbons, Paul</creatorcontrib><creatorcontrib>Ultsch, Mark</creatorcontrib><creatorcontrib>Mortara, Kyle</creatorcontrib><creatorcontrib>Chang, Christine</creatorcontrib><creatorcontrib>Blair, Wade</creatorcontrib><creatorcontrib>Pulk, Rebecca</creatorcontrib><creatorcontrib>Stanley, Mark</creatorcontrib><creatorcontrib>Starovasnik, Melissa</creatorcontrib><creatorcontrib>Williams, David</creatorcontrib><creatorcontrib>Lamers, Maria</creatorcontrib><creatorcontrib>Leonard, Phillip</creatorcontrib><creatorcontrib>Magnuson, Steven</creatorcontrib><creatorcontrib>Liang, Jun</creatorcontrib><creatorcontrib>Eigenbrot, Charles</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Proteins, structure, function, and bioinformatics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tsui, Vickie</au><au>Gibbons, Paul</au><au>Ultsch, Mark</au><au>Mortara, Kyle</au><au>Chang, Christine</au><au>Blair, Wade</au><au>Pulk, Rebecca</au><au>Stanley, Mark</au><au>Starovasnik, Melissa</au><au>Williams, David</au><au>Lamers, Maria</au><au>Leonard, Phillip</au><au>Magnuson, Steven</au><au>Liang, Jun</au><au>Eigenbrot, Charles</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A new regulatory switch in a JAK protein kinase</atitle><jtitle>Proteins, structure, function, and bioinformatics</jtitle><addtitle>Proteins</addtitle><date>2011-02</date><risdate>2011</risdate><volume>79</volume><issue>2</issue><spage>393</spage><epage>401</epage><pages>393-401</pages><issn>0887-3585</issn><eissn>1097-0134</eissn><abstract>Members of the JAK family of protein kinases mediate signal transduction from cytokine receptors to transcription factor activation. Over‐stimulation of these pathways is causative in immune disorders like rheumatoid arthritis, psoriasis, lupus, and Crohn's disease. A search for selective inhibitors of a JAK kinase has led to our characterization of a previously unknown kinase conformation arising from presentation of Tyr962 of TYK2 to an inhibitory small molecule via an H‐bonding interaction. A small minority of protein kinase domains has a Tyrosine residue in this position within the αC‐β4 loop, and it is the only amino acid commonly seen here with H‐bonding potential. These discoveries will aid design of inhibitors that discriminate among the JAK family and more widely among protein kinases. Proteins 2011. © 2010 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>21117080</pmid><doi>10.1002/prot.22889</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-3585 |
| ispartof | Proteins, structure, function, and bioinformatics, 2011-02, Vol.79 (2), p.393-401 |
| issn | 0887-3585 1097-0134 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_822710390 |
| source | MEDLINE; Wiley Online Library All Journals |
| subjects | binding mode Catalytic Domain crystal structure Crystallography, X-Ray Drug Design Humans Isoquinolines - chemistry Models, Molecular Mutation Protein Binding Protein Kinase Inhibitors - chemistry Protein Structure, Tertiary Quinolines - chemistry Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - chemistry selectivity small molecule inhibitor Thiophenes - chemistry TYK2 TYK2 Kinase - antagonists & inhibitors TYK2 Kinase - chemistry |
| title | A new regulatory switch in a JAK protein kinase |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T08%3A21%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20new%20regulatory%20switch%20in%20a%20JAK%20protein%20kinase&rft.jtitle=Proteins,%20structure,%20function,%20and%20bioinformatics&rft.au=Tsui,%20Vickie&rft.date=2011-02&rft.volume=79&rft.issue=2&rft.spage=393&rft.epage=401&rft.pages=393-401&rft.issn=0887-3585&rft.eissn=1097-0134&rft_id=info:doi/10.1002/prot.22889&rft_dat=%3Cproquest_cross%3E3278831381%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1517447215&rft_id=info:pmid/21117080&rfr_iscdi=true |