2cch | pdb_00002cch
The crystal structure of CDK2 cyclin A in complex with a substrate peptide derived from CDC modified with a gamma-linked ATP analogue
Structural highlights
Disease[CDC6_HUMAN] Defects in CDC6 are the cause of Meier-Gorlin syndrome type 5 (MGORS5) [MIM:613805]. MGORS5 is a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.[1] Function[CDC6_HUMAN] Involved in the initiation of DNA replication. Also participates in checkpoint controls that ensure DNA replication is completed before mitosis is initiated. [CCNA2_HUMAN] Essential for the control of the cell cycle at the G1/S (start) and the G2/M (mitosis) transitions. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedPhospho-CDK2/cyclin A, a kinase that is active in cell cycle S phase, contains an RXL substrate recognition site that is over 40 A from the catalytic site. The role of this recruitment site, which enhances substrate affinity and catalytic efficiency, has been investigated using peptides derived from the natural substrates, namely CDC6 and p107, and a bispeptide inhibitor in which the gamma-phosphate of ATP is covalently attached by a linker to the CDC6 substrate peptide. X-ray studies with a 30-residue CDC6 peptide in complex with pCDK2/cyclin A showed binding of a dodecamer peptide at the recruitment site and a heptapeptide at the catalytic site, but no density for the linking 11 residues. Kinetic studies established that the CDC6 peptide had an 18-fold lower Km compared with heptapeptide substrate and that this effect required the recruitment peptide to be covalently linked to the substrate peptide. X-ray studies with the CDC6 bispeptide showed binding of the dodecamer at the recruitment site and the modified ATP in two alternative conformations at the catalytic site. The CDC6 bispeptide was a potent inhibitor competitive with both ATP and peptide substrate of pCDK2/cyclin A activity against a heptapeptide substrate (Ki = 0.83 nm) but less effective against RXL-containing substrates. We discuss how localization at the recruitment site (KD 0.4 microm) leads to increased catalytic efficiency and the design of a potent inhibitor. The notion of a flexible linker between the sites, which must have more than a minimal number of residues, provides an explanation for recognition and discrimination against different substrates. The role of the phospho-CDK2/cyclin A recruitment site in substrate recognition.,Cheng KY, Noble ME, Skamnaki V, Brown NR, Lowe ED, Kontogiannis L, Shen K, Cole PA, Siligardi G, Johnson LN J Biol Chem. 2006 Aug 11;281(32):23167-79. Epub 2006 May 17. PMID:16707497[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||||
Proteopedia Page Contributors and Editors (what is this?)
- Human
- Large Structures
- Brown, N R
- Cheng, K Y
- Cole, P A
- Johnson, L N
- Kontogiannis, L
- Lowe, E D
- Noble, M E.M
- Shen, K
- Siligardi, G
- Skamnaki, V
- Atp-binding
- Cdk2
- Cell cycle
- Cell division
- Cyclin
- Mitosis
- Nuclear protein
- Peptide specificity
- Phosphorylation
- Polymorphism
- Protein kinase
- Recruitment
- Serine-threonine-protein kinase
- Serine/threonine-protein kinase
- Transferase
