PDBsum entry 1vym

DNA binding protein

PDB id: 1vym

Contents

Protein chain

256 a.a. *

Waters ×141

* Residue conservation analysis

PDB id:

1vym

Name:

DNA binding protein

Title:

Native human pcna

Structure:

Proliferating cell nuclear antigen. Chain: a, b, c. Synonym: pcna, cyclin. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Biol. unit:

Trimer (from PDB file)

Resolution:

2.30Å R-factor: 0.191 R-free: 0.279

Authors:

G.Kontopidis,S.Wu,D.Zheleva,P.Taylor,C.Mcinnes,D.Lane,P.Fischer, M.Walkinshaw

Key ref:

G.Kontopidis et al. (2005). Structural and biochemical studies of human proliferating cell nuclear antigen complexes provide a rationale for cyclin association and inhibitor design. Proc Natl Acad Sci U S A, 102, 1871-1876. PubMed id: 15681588 DOI: 10.1073/pnas.0406540102

Date:

03-May-04 Release date: 13-Jan-05

Protein chains

P12004  (PCNA_HUMAN) -  Proliferating cell nuclear antigen from Homo sapiens

Seq: 261 a.a.

Struc: 256 a.a.

DOI no: 10.1073/pnas.0406540102

Proc Natl Acad Sci U S A 102:1871-1876 (2005)

PubMed id: 15681588

Structural and biochemical studies of human proliferating cell nuclear antigen complexes provide a rationale for cyclin association and inhibitor design.

G.Kontopidis, S.Y.Wu, D.I.Zheleva, P.Taylor, C.McInnes, D.P.Lane, P.M.Fischer, M.D.Walkinshaw.

ABSTRACT

The interactions between the tumor suppressor protein p21WAF1 and the cyclin-dependent kinase (CDK) complexes and with proliferating cell nuclear antigen (PCNA) regulate and coordinate the processes of cell-cycle progression and DNA replication. We present the x-ray crystal structure of PCNA complexed with a 16-mer peptide related to p21 that binds with a Kd of 100 nM. Two additional crystal structures of native PCNA provide previously undescribed structures of uncomplexed human PCNA and show that significant changes on ligand binding include rigidification of a number of flexible regions on the surface of PCNA. In the competitive binding experiments described here, we show that a 20-mer sequence from p21 can be associated simultaneously with PCNA and CDK/cyclin complexes. A structural model for this quaternary complex is presented in which the C-terminal sequence of p21 acts like double-sided tape and docks to both the PCNA and cyclin molecules. The quaternary complex shows little direct interaction between PCNA and cyclin, giving p21 the role of an adaptor molecule. Taken together, the biochemical and structural results delineate a druggable inhibitor site on the surface of PCNA that may be exploited in the design of peptidomimetics, which will act independently of cyclin-groove inhibitors.

Selected figure(s)

Figure 4.
Fig. 4. Alignment of the PCNA structures in complex with the p21-derived peptide 139GRKRRQTSMTDFYHSKRRLIFS160 (green) with PCNA (cyan) (Protein Data Bank ID code 1AXC [PDB] ) and the PL peptide 1SAVLQKKITDYFHPKK16 (orange) with PCNA (blue). Key interacting residues are labeled. The phosphorylation site (S146) is highlighted, and the interaction with D149 (D10) is shown (purple).

Figure 6.
Fig. 6. Quaternary complex of CDK (green), cyclin (red), and PCNA (blue). The model was produced by fitting together the "RRLIF sequences" from the two crystal complexes [PCNA/p21 (Protein Data Bank ID code 1AXC [PDB] ) with the labeled peptide in yellow] and CDK/cyclin/RRLIF (Protein Data Bank ID code 1OKV [PDB] ) with the peptide colored cyan. The exploded view shows that the RRLIF conformations in the cyclin A- and PCNA-bound structures are very similar.

Figures were selected by an automated process.