Mechanism of CDK5/p25 binding by CDK inhibitors
Identifieur interne : 000D03 ( PascalFrancis/Corpus ); précédent : 000D02; suivant : 000D04Mechanism of CDK5/p25 binding by CDK inhibitors
Auteurs : Marina Mapelli ; Lucia Massimiliano ; Claudia Crovace ; Markus A. Seeliger ; Li-Huei Tsai ; Laurent Meijer ; Andrea MusacchioSource :
- Journal of medicinal chemistry : (Print) [ 0022-2623 ] ; 2005.
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 :
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.
pA |
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Format Inist (serveur)
NO : | PASCAL 05-0194644 INIST |
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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:05-0194644Le 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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<s5>11</s5>
</fC03>
<fC03 i1="08" i2="X" l="SPA"><s0>Complejo enzima inhibidor</s0>
<s5>11</s5>
</fC03>
<fC03 i1="09" i2="X" l="FRE"><s0>Purine dérivé</s0>
<s5>13</s5>
</fC03>
<fC03 i1="09" i2="X" l="ENG"><s0>Purine derivatives</s0>
<s5>13</s5>
</fC03>
<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>
</fC03>
<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>
</fC03>
<fC03 i1="11" i2="X" l="FRE"><s0>Oxime</s0>
<s5>15</s5>
</fC03>
<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>
</fN82>
</pA>
</standard>
<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>
</inist>
</record>
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