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

Kontopidis G, Wu SY, Zheleva DI, Taylor P, McInnes C, Lane DP, Fischer PM, Walkinshaw MD
Proc Natl Acad Sci U S A 102 1871-6 (2005)
Related entries: 1vyj, 1vym

Cited: 81 times
EuropePMC logo PMID: 15681588

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.

Reviews - 1w60 mentioned but not cited (1)

  1. Human PCNA Structure, Function and Interactions. González-Magaña A, Blanco FJ. Biomolecules 10 (2020)

Articles - 1w60 mentioned but not cited (5)

  1. Structural and biochemical studies of human proliferating cell nuclear antigen complexes provide a rationale for cyclin association and inhibitor design. Kontopidis G, Wu SY, Zheleva DI, Taylor P, McInnes C, Lane DP, Fischer PM, Walkinshaw MD. Proc. Natl. Acad. Sci. U.S.A. 102 1871-1876 (2005)
  2. Timing of galectin-1 exposure differentially modulates Nipah virus entry and syncytium formation in endothelial cells. Garner OB, Yun T, Pernet O, Aguilar HC, Park A, Bowden TA, Freiberg AN, Lee B, Baum LG. J. Virol. 89 2520-2529 (2015)
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Reviews citing this publication (9)

  1. X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution. Putnam CD, Hammel M, Hura GL, Tainer JA. Q. Rev. Biophys. 40 191-285 (2007)
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  4. The regulation of MDM2 by multisite phosphorylation--opportunities for molecular-based intervention to target tumours? Meek DW, Hupp TR. Semin. Cancer Biol. 20 19-28 (2010)
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  8. DNA Sliding Clamps as Therapeutic Targets. Altieri AS, Kelman Z. Front Mol Biosci 5 87 (2018)
  9. Post-Translational Modifications of PCNA in Control of DNA Synthesis and DNA Damage Tolerance-the Implications in Carcinogenesis. Zhang S, Zhou T, Wang Z, Yi F, Li C, Guo W, Xu H, Cui H, Dong X, Liu J, Song X, Cao L. Int J Biol Sci 17 4047-4059 (2021)

Articles citing this publication (66)

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  37. Streamlined, automated protocols for the production of milligram quantities of untagged recombinant human cyclophilin-A (hCypA) and untagged human proliferating cell nuclear antigen (hPCNA) using AKTAxpress. Ludwig C, Wear MA, Walkinshaw MD. Protein Expr. Purif. 71 54-61 (2010)
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  39. Crystal structure of the shrimp proliferating cell nuclear antigen: structural complementarity with WSSV DNA polymerase PIP-box. Carrasco-Miranda JS, Lopez-Zavala AA, Arvizu-Flores AA, Garcia-Orozco KD, Stojanoff V, Rudiño-Piñera E, Brieba LG, Sotelo-Mundo RR. PLoS ONE 9 e94369 (2014)
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  54. Recognition of a Key Anchor Residue by a Conserved Hydrophobic Pocket Ensures Subunit Interface Integrity in DNA Clamps. Perumal SK, Xu X, Yan C, Ivanov I, Benkovic SJ. J Mol Biol 431 2493-2510 (2019)
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