p53—A Natural Cancer Killer: Structural Insights and Therapeutic Concepts

Römer, Lin; Klein, Christian; Dehner, Alexander; Kessler, Horst; Büchner, Johannes

doi:10.1002/anie.200600611

Cited by 102 publications

(71 citation statements)

References 319 publications

(351 reference statements)

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“…Pharmacological restoration of p53 function should, therefore, result in tumor regression, as supported by two recent studies on transgenic mice (Ventura et al 2007;Xue et al 2007). Although various p53-activating compounds have been reported from screening of chemical libraries, the actual mechanism of action of many of these compounds is, frustratingly, largely unresolved (Issaeva et al 2004;Krajewski et al 2005;Romer et al 2006;Vazquez et al 2008). A good example is the compound PRIMA-1MET (Bykov et al 2002;Zache et al 2008), which has proven antitumor activity and is currently in phase I of clinical trials, yet its mode of action is still unclear.…”

Section: Exploiting Structural Information For Cancer Therapymentioning

confidence: 99%

The Tumor Suppressor p53: From Structures to Drug Discovery

Joerger

Fersht²

2010

Cold Spring Harbor Perspectives in Biology

299

280

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Even 30 years after its discovery, the tumor suppressor protein p53 is still somewhat of an enigma. p53's intimate and multifaceted role in the cell cycle is mirrored in its equally complex structural biology that is being unraveled only slowly. Here, we discuss key structural aspects of p53 function and its inactivation by oncogenic mutations. Concerted action of folded and intrinsically disordered domains of the highly dynamic p53 protein provides binding promiscuity and specificity, allowing p53 to process a myriad of cellular signals to maintain the integrity of the human genome. Importantly, progress in elucidating the structural biology of p53 and its partner proteins has opened various avenues for structure-guided rescue of p53 function in tumors. These emerging anticancer strategies include targeting mutant-specific lesions on the surface of destabilized cancer mutants with small molecules and selective inhibition of p53's degradative pathways.

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Section: Exploiting Structural Information For Cancer Therapymentioning

confidence: 99%

The Tumor Suppressor p53: From Structures to Drug Discovery

Joerger

Fersht²

2010

Cold Spring Harbor Perspectives in Biology

299

280

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“…1,2 In stressed cells the MDM2-p53 equilibrium shifts towards dissociation as a result of post-translational modifications (PTM), e.g., phosphorylations. This leads to the accumulation of p53 that triggers cell repair or apoptotic pathways.…”

Section: Introductionmentioning

confidence: 99%

Chemical states of the N-terminal “lid” of MDM2 regulate p53 binding: Simulations reveal complexities of modulation

Dastidar¹,

Raghunathan²,

Nicholson³

et al. 2011

Cell Cycle

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“…p53 is a homotetramer, with folded tetramerization and core domains that are linked together and flanked by intrinsically disordered (or natively unfolded) domains at the N and C termini (1,2). As such, with 37% of its structure intrinsically disordered, p53 is typical of the structural content of the human proteome.…”

mentioning

confidence: 99%

Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain

Wells

Tidow

Rutherford

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

380

411

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Proteins with intrinsically disordered domains are implicated in a vast range of biological processes, especially in cell signaling and regulation. Having solved the quaternary structure of the folded domains in the tumor suppressor p53 by a multidisciplinary approach, we have now determined the average ensemble structure of the intrinsically disordered N-terminal transactivation domain (TAD) by using residual dipolar couplings (RDCs) from NMR spectroscopy and small-angle x-ray scattering (SAXS). Remarkably, not only were we able to measure RDCs of the isolated TAD, but we were also able to do so for the TAD in both the full-length tetrameric p53 protein and in its complex with a specific DNA response element. We determined the orientation of the TAD ensemble relative to the core domain, found that the TAD was stiffer in the proline-rich region (residues 64 -92), which has a tendency to adopt a polyproline II (PPII) structure, and projected the TAD away from the core. We located the TAD in SAXS experiments on a complex between tetrameric p53 and four Taz2 domains that bind tightly to the TAD (residues 1-57) and acted as ''reporters.'' The p53-Taz2 complex was an extended cross-shaped structure. The quality of the SAXS data enabled us to model the disordered termini and the folded domains in the complex with DNA. The core domains enveloped the response element in the center of the molecule, with the Taz2-bound TADs projecting outward from the core.hybrid methods ͉ natively unfolded ͉ protein ͉ residual dipolar coupling ͉ small-angle x-ray scattering T he tumor suppressor p53 is a multifunctional protein that plays vital roles in maintaining the integrity of the human genome, controlling apoptosis, cell-cycle arrest, and DNA repair (1). p53 is a homotetramer, with folded tetramerization and core domains that are linked together and flanked by intrinsically disordered (or natively unfolded) domains at the N and C termini (1, 2). As such, with 37% of its structure intrinsically disordered, p53 is typical of the structural content of the human proteome. More than 30% of eukaryotic genomes encode contiguous unfolded regions longer than 30 aa in length, and up to 80% in cancer-associated proteins (3). This new class of intrinsically disordered proteins (IDPs) is involved in a vast range of cellular processes, including molecular recognition, transcription and transposition, packaging, repair and replication, as well as signaling, cell cycle control, multiprotein complex assembly, and endocytosis. Many partly or fully disordered proteins undergo conformational transitions to folded forms only on interaction with a target ligand (4). An intrinsically disordered domain is possibly an essential structural feature that facilitates promiscuous binding to many partner proteins and is also readily accessible for posttranslational modification that modulates binding.Solving the structures of proteins with intrinsically disordered domains now represents a major stumbling block in relating structure and biological function. Class...

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p53—A Natural Cancer Killer: Structural Insights and Therapeutic Concepts

Cited by 102 publications

References 319 publications

The Tumor Suppressor p53: From Structures to Drug Discovery

The Tumor Suppressor p53: From Structures to Drug Discovery

Chemical states of the N-terminal “lid” of MDM2 regulate p53 binding: Simulations reveal complexities of modulation

Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain

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