9fzb

Human p53 DNA-binding domain bound to DARPin C10-H82R

spinqualitylabelsall models 9fzb, resolution 1.44Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9fzb is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.44Å Ligands: EDO, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease P53_HUMAN Note=TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma. Defects in TP53 are a cause of esophageal cancer (ESCR) [MIM:133239. Defects in TP53 are a cause of Li-Fraumeni syndrome (LFS) [MIM:151623. LFS is an autosomal dominant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers. Defects in TP53 are involved in head and neck squamous cell carcinomas (HNSCC) [MIM:275355; also known as squamous cell carcinoma of the head and neck. Defects in TP53 are a cause of lung cancer (LNCR) [MIM:211980. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. Defects in TP53 are a cause of choroid plexus papilloma (CPLPA) [MIM:260500. Choroid plexus papilloma is a slow-growing benign tumor of the choroid plexus that often invades the leptomeninges. In children it is usually in a lateral ventricle but in adults it is more often in the fourth ventricle. Hydrocephalus is common, either from obstruction or from tumor secretion of cerebrospinal fluid. If it undergoes malignant transformation it is called a choroid plexus carcinoma. Primary choroid plexus tumors are rare and usually occur in early childhood. Defects in TP53 are a cause of adrenocortical carcinoma (ADCC) [MIM:202300. ADCC is a rare childhood tumor of the adrenal cortex. It occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome and is a component tumor in Li-Fraumeni syndrome. Defects in TP53 are the cause of susceptibility to basal cell carcinoma 7 (BCC7) [MIM:614740. A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. It is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter. Function P53_HUMAN Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; te function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seem to have to effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Publication Abstract from PubMed Infection of cells with high-risk strains of the human papillomavirus (HPV) causes cancer in various types of epithelial tissue. HPV infections are responsible for ~4.5% of all cancers worldwide. Tumorigenesis is based on the inactivation of key cellular control mechanisms by the viral proteins E6 and E7. The HPV E6 protein interacts with the cellular E3 ligase E6AP, and this complex binds to the p53 DNA-binding domain, which results in degradation of p53. Inhibition of this interaction has the potential to reactivate p53, thus preventing oncogenic transformation. Here we describe the characterization of a designed ankyrin repeat protein that binds to the same site as the HPV E6 protein, thereby displacing the E3 ligase and stabilizing p53. Interaction with the designed ankyrin repeat protein does not affect p53 DNA binding or the crucial MDM2 negative feedback loop but reactivates a p53-dependent transcriptional program in HeLa (HPV18-positive) and SiHa (HPV16-positive) cells, suggesting a potential therapeutic use. DARPin-induced reactivation of p53 in HPV-positive cells.,Munick P, Strubel A, Balourdas DI, Funk JS, Mernberger M, Osterburg C, Dreier B, Schaefer JV, Tuppi M, Yuksel B, Schafer B, Knapp S, Pluckthun A, Stiewe T, Joerger AC, Dotsch V Nat Struct Mol Biol. 2025 Jan 9. doi: 10.1038/s41594-024-01456-7. PMID:39789211 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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