PDBsum entry 1ihb

Cell cycle inhibitor

PDB id

1ihb

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Contents

			Protein chain

					156 a.a. *

			Waters ×207

* Residue conservation analysis

PDB id:

1ihb

Links

Name:

Cell cycle inhibitor

Title:

Crystal structure of p18-ink4c(ink6)

Structure:

Cyclin-dependent kinase 6 inhibitor. Chain: a, b. Synonym: p18-ink4c(ink6). Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21. Gene: p18-ink4c(ink6). Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.95Å

R-factor:

0.209

R-free:

0.289

Authors:

V.Ravichandran,K.Swaminathan,R.Marmorstein

Key ref:

R.Venkataramani et al. (1998). Crystal structure of the CDK4/6 inhibitory protein p18INK4c provides insights into ankyrin-like repeat structure/function and tumor-derived p16INK4 mutations. Nat Struct Biol, 5, 74-81. PubMed id: 9437433

Date:

25-Oct-97

Release date:

02-Dec-98

PROCHECK

	Headers

	References

Protein chains

P42773 (CDN2C_HUMAN) - Cyclin-dependent kinase 4 inhibitor C from Homo sapiens

Seq: Struc:					168 a.a. 156 a.a.

Key:

PfamA domain

Secondary structure

CATH domain

	Nat Struct Biol 5:74-81 (1998)
PubMed id: 9437433

Crystal structure of the CDK4/6 inhibitory protein p18INK4c provides insights into ankyrin-like repeat structure/function and tumor-derived p16INK4 mutations.
R.Venkataramani, K.Swaminathan, R.Marmorstein.

ABSTRACT

p18INK4c is a member of a family of INK4 proteins that function to arrest the G1 to S cell cycle transition by inhibiting the activity of the cyclin-dependent kinases 4 and 6. The X-ray crystal structure of the human p18INK4c protein to a resolution of 1.95 A reveals an elongated molecule comprised of five contiguous 32- or 33-residue ankyrin-like repeat units. Each ankyrin-like repeat contains a beta-strand helix-turn-helix extended strand beta-strand motif that associates with neighboring motifs through beta-sheet, and helical bundle interactions. Conserved ankyrin-like repeat residues function to facilitate the ankyrin repeat fold and the tertiary interactions between neighboring repeat units. A large percentage of residues that are conserved among INK4 proteins and that map to positions of tumor-derived p16INK4 mutations play important roles in protein stability. A subset of these residues suggest an INK4 binding surface for the cyclin-dependent kinases 4 and 6. This surface is centered around a region that shows structural features uncharacteristic of ankyrin-like repeat units.

Literature references that cite this PDB file's key reference

PubMed id

Reference

19260062

C.Kannengiesser, S.Brookes, A.G.del Arroyo, D.Pham, J.Bombled, M.Barrois, O.Mauffret, M.F.Avril, A.Chompret, G.M.Lenoir, A.Sarasin, G.Peters, B.Bressac-de Paillerets, F.Boitier, V.Bonadonna, J.M.Bonnetblanc, J.Chiesa, I.Coupier, S.Dalle, F.Grange, B.Guillot, P.Joly, C.Lasset, D.Leroux, J.M.Limacher, M.Longy, T.Martin-Denavit, L.Thomas, and P.Vabres (2009).
Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients.

Hum Mutat, 30, 564-574.

18942719

W.van Veelen, R.Klompmaker, M.Gloerich, C.J.van Gasteren, E.Kalkhoven, R.Berger, C.J.Lips, R.H.Medema, J.W.Höppener, and D.S.Acton (2009).
P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development.

Int J Cancer, 124, 339-345.

18481120

P.Sklenovský, P.Banás, and M.Otyepka (2008).
Two C-terminal ankyrin repeats form the minimal stable unit of the ankyrin repeat protein p18INK4c.

J Mol Model, 14, 747-759.

16584130

J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.

AAPS J, 8, E204-E221.

15910504

L.Tan, X.Y.Fu, S.Q.Liu, H.H.Li, Y.Hong, M.C.Wu, and H.Y.Wang (2005).
Expression of p28GANK and its correlation with RB in human hepatocellular carcinoma.

Liver Int, 25, 667-676.

15215520

C.H.Croy, S.Bergqvist, T.Huxford, G.Ghosh, and E.A.Komives (2004).
Biophysical characterization of the free IkappaBalpha ankyrin repeat domain in solution.

Protein Sci, 13, 1767-1777.

12566564

A.Kohl, H.K.Binz, P.Forrer, M.T.Stumpp, A.Plückthun, and M.G.Grütter (2003).
Designed to be stable: crystal structure of a consensus ankyrin repeat protein.

Proc Natl Acad Sci U S A, 100, 1700-1705.

PDB code:

1mj0

12517341

K.S.Tang, A.R.Fersht, and L.S.Itzhaki (2003).
Sequential unfolding of ankyrin repeats in tumor suppressor p16.

Structure, 11, 67-73.

14573873

M.E.Zweifel, D.J.Leahy, F.M.Hughson, and D.Barrick (2003).
Structure and stability of the ankyrin domain of the Drosophila Notch receptor.

Protein Sci, 12, 2622-2632.

PDB code:

1ot8

12686541

S.Malek, D.B.Huang, T.Huxford, S.Ghosh, and G.Ghosh (2003).
X-ray crystal structure of an IkappaBbeta x NF-kappaB p65 homodimer complex.

J Biol Chem, 278, 23094-23100.

PDB codes:

1k3z 1oy3

12456646

P.Michaely, D.R.Tomchick, M.Machius, and R.G.Anderson (2002).
Crystal structure of a 12 ANK repeat stack from human ankyrinR.

EMBO J, 21, 6387-6396.

PDB code:

1n11

12370184

R.N.Venkataramani, T.K.MacLachlan, X.Chai, W.S.El-Deiry, and R.Marmorstein (2002).
Structure-based design of p18INK4c proteins with increased thermodynamic stability and cell cycle inhibitory activity.

J Biol Chem, 277, 48827-48833.

PDB codes:

1mx2 1mx4 1mx6

12124774

V.Bazan, I.Zanna, M.Migliavacca, M.T.Sanz-Casla, M.L.Maestro, S.Corsale, M.Macaluso, G.Dardanoni, S.Restivo, P.L.Quintela, R.Bernaldez, S.Salerno, V.Morello, R.M.Tomasino, N.Gebbia, and A.Russo (2002).
Prognostic significance of p16INK4a alterations and 9p21 loss of heterozygosity in locally advanced laryngeal squamous cell carcinoma.

J Cell Physiol, 192, 286-293.

11485924

J.Boström, B.Meyer-Puttlitz, M.Wolter, B.Blaschke, R.G.Weber, P.Lichter, K.Ichimura, V.P.Collins, and G.Reifenberger (2001).
Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas.

Am J Pathol, 159, 661-669.

11746222

L.Janda, J.Damborský, G.A.Rezniczek, and G.Wiche (2001).
Plectin repeats and modules: strategic cysteines and their presumed impact on cytolinker functions.

Bioessays, 23, 1064-1069.

10892805

C.Yuan, T.L.Selby, J.Li, I.J.Byeon, and M.D.Tsai (2000).
Tumor suppressor INK4: refinement of p16INK4A structure and determination of p15INK4B structure by comparative modeling and NMR data.

Protein Sci, 9, 1120-1128.

PDB code:

1dc2

11124804

P.D.Jeffrey, L.Tong, and N.P.Pavletich (2000).
Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors.

Genes Dev, 14, 3115-3125.

PDB code:

1g3n

10022885

B.B.McConnell, F.J.Gregory, F.J.Stott, E.Hara, and G.Peters (1999).
Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes.

Mol Cell Biol, 19, 1981-1989.

10410794

C.Wolberger (1999).
Multiprotein-DNA complexes in transcriptional regulation.

Annu Rev Biophys Biomol Struct, 28, 29-56.

10607671

J.A.Endicott, M.E.Noble, and J.A.Tucker (1999).
Cyclin-dependent kinases: inhibition and substrate recognition.

Curr Opin Struct Biol, 9, 738-744.

10074345

J.Li, I.J.Byeon, K.Ericson, M.J.Poi, P.O'Maille, T.Selby, and M.D.Tsai (1999).
Tumor suppressor INK4: determination of the solution structure of p18INK4C and demonstration of the functional significance of loops in p18INK4C and p16INK4A.

Biochemistry, 38, 2930-2940.

PDB code:

1bu9

10468583

M.M.Georgescu, K.H.Kirsch, T.Akagi, T.Shishido, and H.Hanafusa (1999).
The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region.

Proc Natl Acad Sci U S A, 96, 10182-10187.

10431175

S.G.Sedgwick, and S.J.Smerdon (1999).
The ankyrin repeat: a diversity of interactions on a common structural framework.

Trends Biochem Sci, 24, 311-316.

9874770

S.Simeonidis, D.Stauber, G.Chen, W.A.Hendrickson, and D.Thanos (1999).
Mechanisms by which IkappaB proteins control NF-kappaB activity.

Proc Natl Acad Sci U S A, 96, 49-54.

11232330

T.Huxford, S.Malek, and G.Ghosh (1999).
Structure and mechanism in NF-kappa B/I kappa B signaling.

Cold Spring Harb Symp Quant Biol, 64, 533-540.

9794820

C.Wolberger (1998).
Combinatorial transcription factors.

Curr Opin Genet Dev, 8, 552-559.

9546211

K.R.Ely, and R.Kodandapani (1998).
Ankyrin(g) ETS domains to DNA.

Nat Struct Biol, 5, 255-259.

9841670

M.D.Mendenhall, and A.E.Hodge (1998).
Regulation of Cdc28 cyclin-dependent protein kinase activity during the cell cycle of the yeast Saccharomyces cerevisiae.

Microbiol Mol Biol Rev, 62, 1191-1243.

9823374

M.Ruas, and G.Peters (1998).
The p16INK4a/CDKN2A tumor suppressor and its relatives.

Biochim Biophys Acta, 1378, F115-F177.

9461066

N.Q.McDonald, and G.Peters (1998).
Ankyrin for clues about the function of p16INK4a.

Nat Struct Biol, 5, 85-88.

9782052

R.Baumgartner, C.Fernandez-Catalan, A.Winoto, R.Huber, R.A.Engh, and T.A.Holak (1998).
Structure of human cyclin-dependent kinase inhibitor p19INK4d: comparison to known ankyrin-repeat-containing structures and implications for the dysfunction of tumor suppressor p16INK4a.

Structure, 6, 1279-1290.

PDB code:

1bd8

9738011

S.Malek, T.Huxford, and G.Ghosh (1998).
Ikappa Balpha functions through direct contacts with the nuclear localization signals and the DNA binding sequences of NF-kappaB.

J Biol Chem, 273, 25427-25435.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.