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Furrer, Julien; Enthart, Andreas; Kühlewein, Angelika; Dehner, Alexander; Klein, Christian; Hansen, Silke; Schwaiger, Manfred; Kessler, Horst; Gemmecker, Gerd

doi:10.1023/a:1024044805720

Cited by 6 publications

(6 citation statements)

References 10 publications

(11 reference statements)

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“…In activating transcription, p63 and p73 function similarly to p53. NMR spectroscopic investigations of the p63 DBD have shown a fold similar to that found in this region of p53 86. On the basis of structural similarity, it was expected that their function, regarding tumor suppression, induction of apoptosis, and cell‐cycle control, would also be similar to that of p53 87.…”

Section: Structure and Stability Of P53mentioning

confidence: 79%

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

Römer

Klein

Dehner³

et al. 2006

Angew Chem Int Ed

102

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Every single day, the DNA of each cell in the human body is mutated thousands of times, even in absence of oncogenes or extreme radiation. Many of these mutations could lead to cancer and, finally, death. To fight this, multicellular organisms have evolved an efficient control system with the tumor-suppressor protein p53 as the central element. An intact p53 network ensures that DNA damage is detected early on. The importance of p53 for preventing cancer is highlighted by the fact that p53 is inactivated in more than 50 % of all human tumors. Thus, for good reason, p53 is one of the most intensively studied proteins. Despite the great effort that has been made to characterize this protein, the complex function and the structural properties of p53 are still only partially known. This review highlights basic concepts and recent progress in understanding the structure and regulation of p53, focusing on emerging new mechanistic and therapeutic concepts.

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Section: Structure and Stability Of P53mentioning

confidence: 79%

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

Römer

Klein

Dehner³

et al. 2006

Angew Chem Int Ed

102

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“…Using NMR methods we could further complement our resonance assignment ( Fig. 1a ) 38 for all backbone and side chain atoms, with the exception of the segment S233–V238 (S262–V267 according to SwissProt accession code Q9H3D4), where the corresponding backbone amide signals could not be observed in the 2D-[ 15 N, 1 H] TROSY spectrum, most likely due to unfavorable exchange processes. NOE-derived distance restraints extracted from a set of 2D and 3D NOESY spectra ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Backbone sequential assignment was completed using standard triple resonance experiments based on earlier results38.Aliphatic side chain assignments were done using H(C)CH- and (H)CCH-COSY67 experiments. The use of 13 C-TOCSY-sidechain experiments was beneficial only for the most slowly relaxing amino acids.…”

Section: Methodsmentioning

confidence: 99%

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Solution structure and binding specificity of the p63 DNA binding domain

Enthart

Klein

Dehner

et al. 2016

Sci Rep

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p63 is a close homologue of p53 and, together with p73, is grouped into the p53 family of transcription factors. p63 is known to be involved in the induction of controlled apoptosis important for differentiation processes, germ line integrity and development. Despite its high homology to p53, especially within the DNA binding domain (DBD), p63-DBD does not show cooperative DNA binding properties and is significantly more stable against thermal and chemical denaturation. Here, we determined the solution structure of p63-DBD and show that it is markedly less dynamic than p53-DBD. In addition, we also investigate the effect of a double salt bridge present in p53-DBD, but not in p63-DBD on the cooperative binding behavior and specificity to various DNA sites. Restoration of the salt bridges in p63-DBD by mutagenesis leads to enhanced binding affinity to p53-specific, but not p63-specific response elements. Furthermore, we show that p63-DBD is capable of binding to anti-apoptotic BclxL via its DNA binding interface, a feature that has only been shown for p53 so far. These data suggest that all p53 family members - despite alterations in the specificity and binding affinity - are capable of activating pro-apoptotic pathways in a tissue specific manner.

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“…p63 und p73 funktionieren bei der Aktivierung der Transkription wie p53. NMR‐Untersuchungen der DBD von p63 ergaben eine Faltung ähnlich der von p53 in dieser Region 86. Wegen der strukturellen Ähnlichkeit wurde erwartet, dass die Funktionen von p63 und p73 hinsichtlich der Unterdrückung von Tumoren, Induktion der Apoptose und Kontrolle des Zellzyklus auch vergleichbar zu jener von p53 sind 87.…”

Section: Struktur Und Stabilität Von P53unclassified

p53 – ein natürlicher Krebskiller: Einsichten in die Struktur und Therapiekonzepte

Römer

Klein²,

Dehner³

et al. 2006

Angewandte Chemie

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Jeden Tag mutiert die DNA einer jeden Zelle im menschlichen Körper – sogar in Abwesenheit von Onkogenen oder extremer Strahlung – tausende Male. Viele dieser Mutationen würden zu Krebs und schließlich zum Tod führen. Um dem entgegenzuwirken, haben vielzellige Organismen ein effizientes Kontrollsystem mit dem Tumorsuppressorprotein p53 als dem zentralen Element entwickelt. Ein intaktes p53‐Netzwerk gewährleistet, dass DNA‐Schäden frühzeitig entdeckt und repariert werden. Die Bedeutung von p53 für die Prävention von Krebs wird dadurch deutlich, dass p53 in mehr als 50 % aller menschlichen Tumoren inaktiviert vorliegt. Aus diesem Grund ist p53 eines der am intensivsten untersuchten Proteine. Trotz der großen Anstrengungen, die unternommen wurden, um dieses Protein zu charakterisieren, sind seine Struktureigenschaften und komplexen Funktionen bisher nur teilweise aufgeklärt. Dieser Aufsatz behandelt vorrangig grundlegende Konzepte und jüngste Fortschritte für das Verständnis der Struktur und Regulierung von p53, unter besonderer Berücksichtigung neuer Therapieansätze.

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Untitled

Cited by 6 publications

References 10 publications

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

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

Solution structure and binding specificity of the p63 DNA binding domain

p53 – ein natürlicher Krebskiller: Einsichten in die Struktur und Therapiekonzepte

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