Multiple modes of ligand recognition: Crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine
Cyclin‐dependent kinases (CDKs) are conserved regulators of the eukaryotic cell cycle with different isoforms controlling specific phases of the cell cycle. Mitogenic or growth inhibitory signals are mediated, respectively, by activation or inhibition of CDKs which phosphorylate proteins associated...
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Veröffentlicht in: | Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 1995-08, Vol.22 (4), p.378-391 |
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creator | Schulze-Gahmen, Ursula Brandsen, Jeroen Jones, Heather D. Morgan, David O. Meijer, Laurent Vesely, Jaroslav Kim, Sung-Hou |
description | Cyclin‐dependent kinases (CDKs) are conserved regulators of the eukaryotic cell cycle with different isoforms controlling specific phases of the cell cycle. Mitogenic or growth inhibitory signals are mediated, respectively, by activation or inhibition of CDKs which phosphorylate proteins associated with the cell cycle. The central role of CDKs in cell cycle regulation makes them a potential new target for inhibitory molecules with anti‐proliferative and/or anti‐neoplastic effects. We describe the crystal structures of the complexes of CDK2 with a weakly specific CDK inhibitor, N6‐(δ2‐isopentenyl)adenine, and a strongly specific inhibitor, olomoucine. Both inhibitors are adenine derivatives and bind in the adenine binding pocket of CDK2, but in an unexpected and different orientation from the adenine of the authentic ligand ATP. The N6‐benzyl substituent in olomoucine binds outside the conserved binding pocket and is most likely responsible for its specificity. The structural information from the CDK2‐olomoucine complex will be useful in directing the search for the next generation inhibitors with improved properties. © 1995 Wiley‐Liss, Inc. |
doi_str_mv | 10.1002/prot.340220408 |
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Mitogenic or growth inhibitory signals are mediated, respectively, by activation or inhibition of CDKs which phosphorylate proteins associated with the cell cycle. The central role of CDKs in cell cycle regulation makes them a potential new target for inhibitory molecules with anti‐proliferative and/or anti‐neoplastic effects. We describe the crystal structures of the complexes of CDK2 with a weakly specific CDK inhibitor, N6‐(δ2‐isopentenyl)adenine, and a strongly specific inhibitor, olomoucine. Both inhibitors are adenine derivatives and bind in the adenine binding pocket of CDK2, but in an unexpected and different orientation from the adenine of the authentic ligand ATP. The N6‐benzyl substituent in olomoucine binds outside the conserved binding pocket and is most likely responsible for its specificity. 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Mitogenic or growth inhibitory signals are mediated, respectively, by activation or inhibition of CDKs which phosphorylate proteins associated with the cell cycle. The central role of CDKs in cell cycle regulation makes them a potential new target for inhibitory molecules with anti‐proliferative and/or anti‐neoplastic effects. We describe the crystal structures of the complexes of CDK2 with a weakly specific CDK inhibitor, N6‐(δ2‐isopentenyl)adenine, and a strongly specific inhibitor, olomoucine. Both inhibitors are adenine derivatives and bind in the adenine binding pocket of CDK2, but in an unexpected and different orientation from the adenine of the authentic ligand ATP. The N6‐benzyl substituent in olomoucine binds outside the conserved binding pocket and is most likely responsible for its specificity. The structural information from the CDK2‐olomoucine complex will be useful in directing the search for the next generation inhibitors with improved properties. © 1995 Wiley‐Liss, Inc.</description><subject>Adenine - analogs & derivatives</subject><subject>Adenine - chemistry</subject><subject>Adenosine Triphosphate - chemistry</subject><subject>Amino Acid Sequence</subject><subject>cancer</subject><subject>CDC2-CDC28 Kinases</subject><subject>CDK inhibitor specificity</subject><subject>Crystallography, X-Ray</subject><subject>Cyclin-Dependent Kinase 2</subject><subject>Cyclin-Dependent Kinases - antagonists & inhibitors</subject><subject>Cyclin-Dependent Kinases - chemistry</subject><subject>drug design</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Humans</subject><subject>Isopentenyladenosine</subject><subject>Kinetin</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Molecular Sequence Data</subject><subject>protein kinase inhibitors</subject><subject>Protein Kinases - drug effects</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - chemistry</subject><subject>Purines - chemistry</subject><subject>Surface Properties</subject><subject>X-ray crystallography</subject><issn>0887-3585</issn><issn>1097-0134</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1DAUhSMEKkNhyw7JK1Zk8E8Sx-yqES2tCq3QAEvLce60po492I6meSJeEw8ZjdixsuVzzqfre4riNcFLgjF9vw0-LVmFKcUVbp8UC4IFLzFh1dNigduWl6xu6-fFixh_YowbwZqT4oRXXHBCFsXvz6NNZmsBDb6HiPwGWXOnXI8CaH_nTDLefUCrMMWkLIopjDqNYXbqSVvjyh624HpwCe2HAePQg3EqAqIo37UfMv4R7Uy6R2frW7SHp53P2r3pTPIhvkPe-sGP2jj4K5voMzKBm6zK4Pz8sni2UTbCq8N5Wnw7_7hefSqvby4uV2fXpaaCtSVR3UYp2jNBGSOiraqeA9SC4aYjuKo4F6qt2i47tKiIEg3GrKakBir0plHstHg7c_NXfo0QkxxM1GCtcuDHKDlvKM0rzsblbNTBxxhgI7fBDCpMkmC5b0bulyGPzeTAmwN57Aboj_ZDFVkXs74zFqb_0OTt15v1v-xyzpqY4PGYVeFBNpzxWv74ciG_12vGWnYlz9kfNlutOw</recordid><startdate>199508</startdate><enddate>199508</enddate><creator>Schulze-Gahmen, Ursula</creator><creator>Brandsen, Jeroen</creator><creator>Jones, Heather D.</creator><creator>Morgan, David O.</creator><creator>Meijer, Laurent</creator><creator>Vesely, Jaroslav</creator><creator>Kim, Sung-Hou</creator><general>Wiley Subscription Services, Inc., A Wiley Company</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>7X8</scope></search><sort><creationdate>199508</creationdate><title>Multiple modes of ligand recognition: Crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine</title><author>Schulze-Gahmen, Ursula ; Brandsen, Jeroen ; Jones, Heather D. ; Morgan, David O. ; Meijer, Laurent ; Vesely, Jaroslav ; Kim, Sung-Hou</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2938-1abfaa2d3923319844d7ee59306b1044779a848b2d3c941a960035215e29cf6a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>Adenine - analogs & derivatives</topic><topic>Adenine - chemistry</topic><topic>Adenosine Triphosphate - chemistry</topic><topic>Amino Acid Sequence</topic><topic>cancer</topic><topic>CDC2-CDC28 Kinases</topic><topic>CDK inhibitor specificity</topic><topic>Crystallography, X-Ray</topic><topic>Cyclin-Dependent Kinase 2</topic><topic>Cyclin-Dependent Kinases - antagonists & inhibitors</topic><topic>Cyclin-Dependent Kinases - chemistry</topic><topic>drug design</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Humans</topic><topic>Isopentenyladenosine</topic><topic>Kinetin</topic><topic>Ligands</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Molecular Sequence Data</topic><topic>protein kinase inhibitors</topic><topic>Protein Kinases - drug effects</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - chemistry</topic><topic>Purines - chemistry</topic><topic>Surface Properties</topic><topic>X-ray crystallography</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schulze-Gahmen, Ursula</creatorcontrib><creatorcontrib>Brandsen, Jeroen</creatorcontrib><creatorcontrib>Jones, Heather D.</creatorcontrib><creatorcontrib>Morgan, David O.</creatorcontrib><creatorcontrib>Meijer, Laurent</creatorcontrib><creatorcontrib>Vesely, Jaroslav</creatorcontrib><creatorcontrib>Kim, Sung-Hou</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>MEDLINE - Academic</collection><jtitle>Proteins, structure, function, and bioinformatics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schulze-Gahmen, Ursula</au><au>Brandsen, Jeroen</au><au>Jones, Heather D.</au><au>Morgan, David O.</au><au>Meijer, Laurent</au><au>Vesely, Jaroslav</au><au>Kim, Sung-Hou</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multiple modes of ligand recognition: Crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine</atitle><jtitle>Proteins, structure, function, and bioinformatics</jtitle><addtitle>Proteins</addtitle><date>1995-08</date><risdate>1995</risdate><volume>22</volume><issue>4</issue><spage>378</spage><epage>391</epage><pages>378-391</pages><issn>0887-3585</issn><eissn>1097-0134</eissn><abstract>Cyclin‐dependent kinases (CDKs) are conserved regulators of the eukaryotic cell cycle with different isoforms controlling specific phases of the cell cycle. Mitogenic or growth inhibitory signals are mediated, respectively, by activation or inhibition of CDKs which phosphorylate proteins associated with the cell cycle. The central role of CDKs in cell cycle regulation makes them a potential new target for inhibitory molecules with anti‐proliferative and/or anti‐neoplastic effects. We describe the crystal structures of the complexes of CDK2 with a weakly specific CDK inhibitor, N6‐(δ2‐isopentenyl)adenine, and a strongly specific inhibitor, olomoucine. Both inhibitors are adenine derivatives and bind in the adenine binding pocket of CDK2, but in an unexpected and different orientation from the adenine of the authentic ligand ATP. The N6‐benzyl substituent in olomoucine binds outside the conserved binding pocket and is most likely responsible for its specificity. 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subjects | Adenine - analogs & derivatives Adenine - chemistry Adenosine Triphosphate - chemistry Amino Acid Sequence cancer CDC2-CDC28 Kinases CDK inhibitor specificity Crystallography, X-Ray Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases - antagonists & inhibitors Cyclin-Dependent Kinases - chemistry drug design Enzyme Inhibitors - chemistry Humans Isopentenyladenosine Kinetin Ligands Models, Molecular Molecular Conformation Molecular Sequence Data protein kinase inhibitors Protein Kinases - drug effects Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - chemistry Purines - chemistry Surface Properties X-ray crystallography |
title | Multiple modes of ligand recognition: Crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine |
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