1h27: Difference between revisions
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==Overview== | ==Overview== | ||
Progression through S phase of the eukaryotic cell cycle is regulated by, the action of the cyclin dependent protein kinase 2 (CDK2) in association, with cyclin A. CDK2/cyclin A phosphorylates numerous substrates. Substrate, specificity often employs a dual recognition strategy in which the, sequence flanking the phospho-acceptor site (Ser.Pro.X.Arg/Lys) is, recognized by CDK2, while the cyclin A component of the complex contains a, hydrophobic site that binds Arg/Lys.X.Leu ("RXL" or "KXL") substrate, recruitment motifs. To determine additional sequence specificity motifs, around the RXL sequence, we have performed X-ray crystallographic studies, at 2.3 A resolution and isothermal calorimetry measurements on complexes, of phospho-CDK2/cyclin A with a recruitment peptide derived from E2F1 ... | Progression through S phase of the eukaryotic cell cycle is regulated by, the action of the cyclin dependent protein kinase 2 (CDK2) in association, with cyclin A. CDK2/cyclin A phosphorylates numerous substrates. Substrate, specificity often employs a dual recognition strategy in which the, sequence flanking the phospho-acceptor site (Ser.Pro.X.Arg/Lys) is, recognized by CDK2, while the cyclin A component of the complex contains a, hydrophobic site that binds Arg/Lys.X.Leu ("RXL" or "KXL") substrate, recruitment motifs. To determine additional sequence specificity motifs, around the RXL sequence, we have performed X-ray crystallographic studies, at 2.3 A resolution and isothermal calorimetry measurements on complexes, of phospho-CDK2/cyclin A with a recruitment peptide derived from E2F1 and, with shorter 11-mer peptides from p53, pRb, p27, E2F1, and p107. The, results show that the cyclin recruitment site accommodates a second, hydrophobic residue either immediately C-terminal or next adjacent to the, leucine of the "RXL" motif and that this site makes important, contributions to the recruitment peptide recognition. The arginine of the, RXL motif contacts a glutamate, Glu220, on the cyclin. In those substrates, that contain a KXL motif, no ionic interactions are observed with the, lysine. The sequences N-terminal to the "RXL" motif of the individual, peptides show no conservation, but nevertheless make common contacts to, the cyclin through main chain interactions. Thus, the recruitment site is, able to recognize diverse but conformationally constrained target, sequences. The observations have implications for the further, identification of physiological substrates of CDK2/cyclin A and the design, of specific inhibitors. | ||
==About this Structure== | ==About this Structure== | ||
1H27 is a | 1H27 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1H27 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: serine/threonine-protein kinase]] | [[Category: serine/threonine-protein kinase]] | ||
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Revision as of 14:51, 5 November 2007
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CDK2/CYCLIN A IN COMPLEX WITH AN 11-RESIDUE RECRUITMENT PEPTIDE FROM P27
OverviewOverview
Progression through S phase of the eukaryotic cell cycle is regulated by, the action of the cyclin dependent protein kinase 2 (CDK2) in association, with cyclin A. CDK2/cyclin A phosphorylates numerous substrates. Substrate, specificity often employs a dual recognition strategy in which the, sequence flanking the phospho-acceptor site (Ser.Pro.X.Arg/Lys) is, recognized by CDK2, while the cyclin A component of the complex contains a, hydrophobic site that binds Arg/Lys.X.Leu ("RXL" or "KXL") substrate, recruitment motifs. To determine additional sequence specificity motifs, around the RXL sequence, we have performed X-ray crystallographic studies, at 2.3 A resolution and isothermal calorimetry measurements on complexes, of phospho-CDK2/cyclin A with a recruitment peptide derived from E2F1 and, with shorter 11-mer peptides from p53, pRb, p27, E2F1, and p107. The, results show that the cyclin recruitment site accommodates a second, hydrophobic residue either immediately C-terminal or next adjacent to the, leucine of the "RXL" motif and that this site makes important, contributions to the recruitment peptide recognition. The arginine of the, RXL motif contacts a glutamate, Glu220, on the cyclin. In those substrates, that contain a KXL motif, no ionic interactions are observed with the, lysine. The sequences N-terminal to the "RXL" motif of the individual, peptides show no conservation, but nevertheless make common contacts to, the cyclin through main chain interactions. Thus, the recruitment site is, able to recognize diverse but conformationally constrained target, sequences. The observations have implications for the further, identification of physiological substrates of CDK2/cyclin A and the design, of specific inhibitors.
About this StructureAbout this Structure
1H27 is a Protein complex structure of sequences from Homo sapiens. Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
Specificity determinants of recruitment peptides bound to phospho-CDK2/cyclin A., Lowe ED, Tews I, Cheng KY, Brown NR, Gul S, Noble ME, Gamblin SJ, Johnson LN, Biochemistry. 2002 Dec 31;41(52):15625-34. PMID:12501191
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