ParkinsonFranceV1, PascalFrancis, Corpus, bibRecord, 000D03

Mechanism of CDK5/p25 binding by CDK inhibitors

Identifieur interne : 000D03 ( PascalFrancis/Corpus ); précédent : 000D02; suivant : 000D04

Mechanism of CDK5/p25 binding by CDK inhibitors

Auteurs : Marina Mapelli ; Lucia Massimiliano ; Claudia Crovace ; Markus A. Seeliger ; Li-Huei Tsai ; Laurent Meijer ; Andrea Musacchio

Source :

Journal of medicinal chemistry : (Print) [ 0022-2623 ] ; 2005.

RBID : Pascal:05-0194644

Descripteurs français

Pascal (Inist)
- Activité biologique, Transduction signal, Inhibiteur enzyme, Protein kinase, Mécanisme action, Modèle moléculaire, Structure cristalline, Complexe enzyme inhibiteur, Purine dérivé, Indole dérivé, Oxime, Inhibiteur cdk5, Purine(6-benzylamino-2-[1-(hydroxyméthyl)propylamino]-9-isopropyl), Pyrrolo[2,3-b]pyrazine dérivé, Pyrrolopyrazine, Aloisine A, Indirubine oxime.

English descriptors

KwdEn :
- Biological activity, Crystalline structure, Enzyme inhibitor, Indole derivatives, Inhibitor enzyme complex, Mechanism of action, Molecular model, Oxime, Protein kinase, Purine derivatives, Signal transduction.

Abstract

The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 Å, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

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A08	`01`	`1`	`ENG`	`@1 Mechanism of CDK5/p25 binding by CDK inhibitors`
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A11	`02`	`1`		`@1 MASSIMILIANO (Lucia)`
A11	`03`	`1`		`@1 CROVACE (Claudia)`
A11	`04`	`1`		`@1 SEELIGER (Markus A.)`
A11	`05`	`1`		`@1 TSAI (Li-Huei)`
A11	`06`	`1`		`@1 MEIJER (Laurent)`
A11	`07`	`1`		`@1 MUSACCHIO (Andrea)`
A14	`01`			`@1 Structural Biology Unit, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435 @2 20141 Milan @3 ITA @Z 1 aut. @Z 2 aut. @Z 3 aut. @Z 7 aut.`
A14	`02`			`@1 Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California Berkeley @2 Berkeley, California 94720-3202 @3 USA @Z 3 aut.`
A14	`03`			`@1 Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 77 Avenue Louis Pasteur @2 Boston, Massachusetts 02115 @3 USA @Z 4 aut.`
A14	`04`			`@1 Cell Cycle Group, Station Biologique, B.P. 74 @2 29682 Roscoff, Bretagne @3 FRA @Z 5 aut. @Z 6 aut.`
A20				`@1 671-679`
A21				`@1 2005`
A23	`01`			`@0 ENG`
A43	`01`			`@1 INIST @2 9165 @5 354000126647600050`
A44				`@0 0000 @1 © 2005 INIST-CNRS. All rights reserved.`
A45				`@0 54 ref.`
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A64	`01`	`1`		`@0 Journal of medicinal chemistry : (Print)`
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C01	`01`		`ENG`	@0 The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 Å, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.
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C03	`02`	`X`	`SPA`	`@0 Transducción señal @5 03`
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Format Inist (serveur)

NO :	PASCAL 05-0194644 INIST
ET :	Mechanism of CDK5/p25 binding by CDK inhibitors
AU :	MAPELLI (Marina); MASSIMILIANO (Lucia); CROVACE (Claudia); SEELIGER (Markus A.); TSAI (Li-Huei); MEIJER (Laurent); MUSACCHIO (Andrea)
AF :	Structural Biology Unit, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435/20141 Milan/Italie (1 aut., 2 aut., 3 aut., 7 aut.); Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California Berkeley/Berkeley, California 94720-3202/Etats-Unis (3 aut.); Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 77 Avenue Louis Pasteur/Boston, Massachusetts 02115/Etats-Unis (4 aut.); Cell Cycle Group, Station Biologique, B.P. 74/29682 Roscoff, Bretagne/France (5 aut., 6 aut.)
DT :	Publication en série; Niveau analytique
SO :	Journal of medicinal chemistry : (Print); ISSN 0022-2623; Coden JMCMAR; Etats-Unis; Da. 2005; Vol. 48; No. 3; Pp. 671-679; Bibl. 54 ref.
LA :	Anglais
EA :	The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 Å, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.
CC :	002B02W
FD :	Activité biologique; Transduction signal; Inhibiteur enzyme; Protein kinase; Mécanisme action; Modèle moléculaire; Structure cristalline; Complexe enzyme inhibiteur; Purine dérivé; Indole dérivé; Oxime; Inhibiteur cdk5; Purine(6-benzylamino-2-[1-(hydroxyméthyl)p ropylamino]-9-isopropyl); Pyrrolo[2,3-b]pyrazine dérivé; Pyrrolopyrazine; Aloisine A; Indirubine oxime
FG :	Transferases; Enzyme
ED :	Biological activity; Signal transduction; Enzyme inhibitor; Protein kinase; Mechanism of action; Molecular model; Crystalline structure; Inhibitor enzyme complex; Purine derivatives; Indole derivatives; Oxime
EG :	Transferases; Enzyme
SD :	Actividad biológica; Transducción señal; Inhibidor enzima; Protein kinase; Mecanismo acción; Modelo molecular; Estructura cristalina; Complejo enzima inhibidor; Purina derivado; Indol derivado; Oxima
LO :	INIST-9165.354000126647600050
ID :	05-0194644

Links to Exploration step

Pascal:05-0194644

Le document en format XML

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<front><div type="abstract" xml:lang="en">The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 Å, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.</div>
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<fA11 i1="01" i2="1"><s1>MAPELLI (Marina)</s1>
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<fA11 i1="02" i2="1"><s1>MASSIMILIANO (Lucia)</s1>
</fA11>
<fA11 i1="03" i2="1"><s1>CROVACE (Claudia)</s1>
</fA11>
<fA11 i1="04" i2="1"><s1>SEELIGER (Markus A.)</s1>
</fA11>
<fA11 i1="05" i2="1"><s1>TSAI (Li-Huei)</s1>
</fA11>
<fA11 i1="06" i2="1"><s1>MEIJER (Laurent)</s1>
</fA11>
<fA11 i1="07" i2="1"><s1>MUSACCHIO (Andrea)</s1>
</fA11>
<fA14 i1="01"><s1>Structural Biology Unit, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435</s1>
<s2>20141 Milan</s2>
<s3>ITA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>7 aut.</sZ>
</fA14>
<fA14 i1="02"><s1>Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California Berkeley</s1>
<s2>Berkeley, California 94720-3202</s2>
<s3>USA</s3>
<sZ>3 aut.</sZ>
</fA14>
<fA14 i1="03"><s1>Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 77 Avenue Louis Pasteur</s1>
<s2>Boston, Massachusetts 02115</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
</fA14>
<fA14 i1="04"><s1>Cell Cycle Group, Station Biologique, B.P. 74</s1>
<s2>29682 Roscoff, Bretagne</s2>
<s3>FRA</s3>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
</fA14>
<fA20><s1>671-679</s1>
</fA20>
<fA21><s1>2005</s1>
</fA21>
<fA23 i1="01"><s0>ENG</s0>
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<s5>354000126647600050</s5>
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<s1>© 2005 INIST-CNRS. All rights reserved.</s1>
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</fA45>
<fA47 i1="01" i2="1"><s0>05-0194644</s0>
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<fA60><s1>P</s1>
</fA60>
<fA61><s0>A</s0>
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<fA64 i1="01" i2="1"><s0>Journal of medicinal chemistry : (Print)</s0>
</fA64>
<fA66 i1="01"><s0>USA</s0>
</fA66>
<fC01 i1="01" l="ENG"><s0>The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 Å, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.</s0>
</fC01>
<fC02 i1="01" i2="X"><s0>002B02W</s0>
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<fC03 i1="01" i2="X" l="FRE"><s0>Activité biologique</s0>
<s5>01</s5>
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<fC03 i1="01" i2="X" l="ENG"><s0>Biological activity</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="SPA"><s0>Actividad biológica</s0>
<s5>01</s5>
</fC03>
<fC03 i1="02" i2="X" l="FRE"><s0>Transduction signal</s0>
<s5>03</s5>
</fC03>
<fC03 i1="02" i2="X" l="ENG"><s0>Signal transduction</s0>
<s5>03</s5>
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<fC03 i1="02" i2="X" l="SPA"><s0>Transducción señal</s0>
<s5>03</s5>
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<fC03 i1="03" i2="X" l="FRE"><s0>Inhibiteur enzyme</s0>
<s5>04</s5>
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<fC03 i1="03" i2="X" l="ENG"><s0>Enzyme inhibitor</s0>
<s5>04</s5>
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<fC03 i1="03" i2="X" l="SPA"><s0>Inhibidor enzima</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="FRE"><s0>Protein kinase</s0>
<s2>FE</s2>
<s5>05</s5>
</fC03>
<fC03 i1="04" i2="X" l="ENG"><s0>Protein kinase</s0>
<s2>FE</s2>
<s5>05</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA"><s0>Protein kinase</s0>
<s2>FE</s2>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="FRE"><s0>Mécanisme action</s0>
<s5>06</s5>
</fC03>
<fC03 i1="05" i2="X" l="ENG"><s0>Mechanism of action</s0>
<s5>06</s5>
</fC03>
<fC03 i1="05" i2="X" l="SPA"><s0>Mecanismo acción</s0>
<s5>06</s5>
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<fC03 i1="06" i2="X" l="FRE"><s0>Modèle moléculaire</s0>
<s5>08</s5>
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<fC03 i1="06" i2="X" l="ENG"><s0>Molecular model</s0>
<s5>08</s5>
</fC03>
<fC03 i1="06" i2="X" l="SPA"><s0>Modelo molecular</s0>
<s5>08</s5>
</fC03>
<fC03 i1="07" i2="X" l="FRE"><s0>Structure cristalline</s0>
<s5>09</s5>
</fC03>
<fC03 i1="07" i2="X" l="ENG"><s0>Crystalline structure</s0>
<s5>09</s5>
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<fC03 i1="07" i2="X" l="SPA"><s0>Estructura cristalina</s0>
<s5>09</s5>
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<fC03 i1="08" i2="X" l="FRE"><s0>Complexe enzyme inhibiteur</s0>
<s5>11</s5>
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<fC03 i1="08" i2="X" l="ENG"><s0>Inhibitor enzyme complex</s0>
<s5>11</s5>
</fC03>
<fC03 i1="08" i2="X" l="SPA"><s0>Complejo enzima inhibidor</s0>
<s5>11</s5>
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<fC03 i1="09" i2="X" l="FRE"><s0>Purine dérivé</s0>
<s5>13</s5>
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<fC03 i1="09" i2="X" l="ENG"><s0>Purine derivatives</s0>
<s5>13</s5>
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<fC03 i1="09" i2="X" l="SPA"><s0>Purina derivado</s0>
<s5>13</s5>
</fC03>
<fC03 i1="10" i2="X" l="FRE"><s0>Indole dérivé</s0>
<s5>14</s5>
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<fC03 i1="10" i2="X" l="ENG"><s0>Indole derivatives</s0>
<s5>14</s5>
</fC03>
<fC03 i1="10" i2="X" l="SPA"><s0>Indol derivado</s0>
<s5>14</s5>
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<fC03 i1="11" i2="X" l="FRE"><s0>Oxime</s0>
<s5>15</s5>
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<fC03 i1="11" i2="X" l="ENG"><s0>Oxime</s0>
<s5>15</s5>
</fC03>
<fC03 i1="11" i2="X" l="SPA"><s0>Oxima</s0>
<s5>15</s5>
</fC03>
<fC03 i1="12" i2="X" l="FRE"><s0>Inhibiteur cdk5</s0>
<s4>INC</s4>
<s5>76</s5>
</fC03>
<fC03 i1="13" i2="X" l="FRE"><s0>Purine(6-benzylamino-2-[1-(hydroxyméthyl)propylamino]-9-isopropyl)</s0>
<s2>NK</s2>
<s4>INC</s4>
<s5>78</s5>
</fC03>
<fC03 i1="14" i2="X" l="FRE"><s0>Pyrrolo[2,3-b]pyrazine dérivé</s0>
<s2>NK</s2>
<s4>INC</s4>
<s5>79</s5>
</fC03>
<fC03 i1="15" i2="X" l="FRE"><s0>Pyrrolopyrazine</s0>
<s4>INC</s4>
<s5>80</s5>
</fC03>
<fC03 i1="16" i2="X" l="FRE"><s0>Aloisine A</s0>
<s4>INC</s4>
<s5>81</s5>
</fC03>
<fC03 i1="17" i2="X" l="FRE"><s0>Indirubine oxime</s0>
<s4>INC</s4>
<s5>83</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE"><s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="01" i2="X" l="ENG"><s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="01" i2="X" l="SPA"><s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="02" i2="X" l="FRE"><s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="02" i2="X" l="ENG"><s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="02" i2="X" l="SPA"><s0>Enzima</s0>
<s2>FE</s2>
</fC07>
<fN21><s1>136</s1>
</fN21>
<fN44 i1="01"><s1>PSI</s1>
</fN44>
<fN82><s1>PSI</s1>
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<server><NO>PASCAL 05-0194644 INIST</NO>
<ET>Mechanism of CDK5/p25 binding by CDK inhibitors</ET>
<AU>MAPELLI (Marina); MASSIMILIANO (Lucia); CROVACE (Claudia); SEELIGER (Markus A.); TSAI (Li-Huei); MEIJER (Laurent); MUSACCHIO (Andrea)</AU>
<AF>Structural Biology Unit, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435/20141 Milan/Italie (1 aut., 2 aut., 3 aut., 7 aut.); Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California Berkeley/Berkeley, California 94720-3202/Etats-Unis (3 aut.); Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 77 Avenue Louis Pasteur/Boston, Massachusetts 02115/Etats-Unis (4 aut.); Cell Cycle Group, Station Biologique, B.P. 74/29682 Roscoff, Bretagne/France (5 aut., 6 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Journal of medicinal chemistry : (Print); ISSN 0022-2623; Coden JMCMAR; Etats-Unis; Da. 2005; Vol. 48; No. 3; Pp. 671-679; Bibl. 54 ref.</SO>
<LA>Anglais</LA>
<EA>The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 Å, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.</EA>
<CC>002B02W</CC>
<FD>Activité biologique; Transduction signal; Inhibiteur enzyme; Protein kinase; Mécanisme action; Modèle moléculaire; Structure cristalline; Complexe enzyme inhibiteur; Purine dérivé; Indole dérivé; Oxime; Inhibiteur cdk5; Purine(6-benzylamino-2-[1-(hydroxyméthyl)p ropylamino]-9-isopropyl); Pyrrolo[2,3-b]pyrazine dérivé; Pyrrolopyrazine; Aloisine A; Indirubine oxime</FD>
<FG>Transferases; Enzyme</FG>
<ED>Biological activity; Signal transduction; Enzyme inhibitor; Protein kinase; Mechanism of action; Molecular model; Crystalline structure; Inhibitor enzyme complex; Purine derivatives; Indole derivatives; Oxime</ED>
<EG>Transferases; Enzyme</EG>
<SD>Actividad biológica; Transducción señal; Inhibidor enzima; Protein kinase; Mecanismo acción; Modelo molecular; Estructura cristalina; Complejo enzima inhibidor; Purina derivado; Indol derivado; Oxima</SD>
<LO>INIST-9165.354000126647600050</LO>
<ID>05-0194644</ID>
</server>
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Mechanism of CDK5/p25 binding by CDK inhibitors

Mechanism of CDK5/p25 binding by CDK inhibitors

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