PDBsum entry 1ap7

Cell cycle inhibitor

PDB id: 1ap7

Contents

Protein chain

168 a.a. *

* Residue conservation analysis

PDB id:

1ap7

Name:

Cell cycle inhibitor

Title:

P19-ink4d from mouse, nmr, 20 structures

Structure:

P19-ink4d. Chain: a. Synonym: cyclin dependent kinase 4 inhibitor d. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Cell_line: bl21. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Transferase gene.

NMR struc:

20 models

Authors:

S.J.Archer,F.Y.Luh,P.J.Domaille,B.O.Smith,E.D.Laue

Key ref:

F.Y.Luh et al. (1997). Structure of the cyclin-dependent kinase inhibitor p19Ink4d. Nature, 389, 999. PubMed id: 9353127 DOI: 10.1038/40202

Date:

25-Jul-97 Release date: 16-Sep-98

Protein chain

Q60773  (CDN2D_MOUSE) -  Cyclin-dependent kinase 4 inhibitor D from Mus musculus

Seq: 166 a.a.

Struc: 168 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1038/40202

Nature 389:999 (1997)

PubMed id: 9353127

Structure of the cyclin-dependent kinase inhibitor p19Ink4d.

F.Y.Luh, S.J.Archer, P.J.Domaille, B.O.Smith, D.Owen, D.H.Brotherton, A.R.Raine, X.Xu, L.Brizuela, S.L.Brenner, E.D.Laue.

ABSTRACT

In cancer, the biochemical pathways that are dominated by the two tumour-suppressor proteins, p53 and Rb, are the most frequently disrupted. Cyclin D-dependent kinases phosphorylate Rb to control its activity and they are, in turn, specifically inhibited by the Ink4 family of cyclin-dependent kinase inhibitors (CDKIs) which cause arrest at the G1 phase of the cell cycle. Mutations in Rb, cyclin D1, its catalytic subunit Cdk4, and the CDKI p16Ink4a, which alter the protein or its level of expression, are all strongly implicated in cancer. This suggests that the Rb 'pathway' is of particular importance. Here we report the structure of the p19Ink4d protein, determined by NMR spectroscopy. The structure indicates that most mutations to the p16Ink4a gene, which result in loss of function, are due to incorrectly folded and/or insoluble proteins. We propose a model for the interaction of Ink4 proteins with D-type cyclin-Cdk4/6 complexes that might provide a basis for the design of therapeutics against cancer. The sequences of the Ink4 family of CDKIs are highly conserved

Selected figure(s)

Figure 1.
Figure 1 Amino-acid sequence of the mouse p19^Ink4d protein showing the homology between different ankyrin repeats (defined as i. n ref. 7, but aligned according to the structure) and between the different members of the Ink4 family of cyclin-dependent kinase inhibitors. Arrows and rectangles indicate the approximate positions of the -strands and -helices, respectively. Selected conserved residues are coloured yellow (core hydrophobic), orange (aspartate and asparagine), green (glycine and proline), red (Asp 71), magenta (histidine) and blue (Lys 43) (see text for details).

Figure 3.
Figure 3 a, Comparison of the structure of p19^Ink4d closest to the mean with that of 53BP2. The structures are shown in the same orientation as those in Fig. 2 and the C carbons of structurally equivalent residues in ankyrins III and IV from p19^Ink4d and II and III from p53BP2 have been superimposed. The surface-exposed residues of the sequence corresponding to the p16^Ink4a peptide fragment (residues 80-99), previously shown partially to mimic the activity of the intact protein, are shown in yellow (ref. 22, and S. Wick, M. Dubay and L.B., unpublished results). The side chains of residues 91 and 92, which, based on alanine scanning mutagenesis in the peptide^22, most influence the interaction with Cdk4 and Cdk6, are shown in dark blue. b, Protein surfaces of the same p19^Ink4d structure (but now rotated 55 ? about the y-axis compared to that shown in a and Fig. 2) and a model of Cdk4/cyclin D1 (B.O.S., unpublished). Cdk4 is shown in white, cyclin D1 in purple, and Lys 22, Arg 24 and residues 95-97 of Cdk4 are in red; a yellow arrow indicates the position of the active site in Cdk4. These plots were generated using MOLSCRIPT29 and GRASP30.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1997, 389, 999-0) copyright 1997.

Figures were selected by the author.