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https://www.readbyqxmd.com/read/28487147/optimal-affinity-enhancement-by-a-conserved-flexible-linker-controls-p53-mimicry-in-mdmx
#1
Wade Borcherds, Andreas Becker, Lihong Chen, Jiandong Chen, Lucía B Chemes, Gary W Daughdrill
MdmX contains an intramolecular binding motif that mimics the binding of the p53 tumor suppressor. This intramolecular binding motif is connected to the p53 binding domain of MdmX by a conserved flexible linker that is 85 residues long. The sequence of this flexible linker has an identity of 51% based on multiple protein sequence alignments of 52 MdmX homologs. We used polymer statistics to estimate a global KD value for p53 binding to MdmX in the presence of the flexible linker and the intramolecular binding motif by assuming the flexible linker behaves as a wormlike chain...
May 23, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28482147/1-4-5-trisubstituted-imidazole-based-p53-mdm2-mdmx-antagonists-with-aliphatic-linkers-for-conjugation-with-biological-carriers
#2
Aleksandra Twarda-Clapa, Sylwia Krzanik, Katarzyna Kubica, Katarzyna Guzik, Beata Labuzek, Constantinos G Neochoritis, Kareem Khoury, Kaja Kowalska, Miroslawa Czub, Grzegorz Dubin, Alexander Dömling, Lukasz Skalniak, Tad A Holak
The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TP53 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers...
May 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28440085/actinomycin-d-synergistically-enhances-the-cytotoxicity-of-cddp-on-kb-cells-by-activating-p53-via-decreasing-p53-mdm2-complex
#3
Lin Wang, Xiao-Cong Pang, Zi-Ru Yu, Sheng-Qian Yang, Ai-Lin Liu, Jin-Hua Wang, Guan-Hua Du
The aim of this study is to investigate the synergism of low dose of actinomycin D (LDActD) to the cytotoxicity of cisplatin (CDDP) on KB cells. The role of P53 reactivation by LDActD in the synergism and its mechanism were further studied. Cell viability was determined by MTT assay. Apoptosis was determined by AnnexinV-FITC/PI staining. Mitochondrial membrane potential (MMP) was detected by JC-1 staining. Expression of proteins was detected by Western blotting (WB) and/or immunofluorescence (IF). Molecular docking of actinomycin D (ACTD) to Mouse double minute 2 homolog (MDM2) and Mouse double minute 2 homolog X (MDMX)...
April 25, 2017: Journal of Asian Natural Products Research
https://www.readbyqxmd.com/read/28425639/designing-dual-inhibitors-of-mdm2-mdmx-unexpected-coupling-of-water-with-gatekeeper-y100-99
#4
Xiong An Lee, Chandra Verma, Adelene Y L Sim
Mdm2 and MdmX share high structural similarity in their N-terminal domains, yet dual inhibitors are challenging to design due to differences in the conformations of the binding pockets, and notably of the proposed gatekeeper residue, Y100/99. Analysis of crystal structures and molecular dynamics (MD) simulations of complexes of Mdm2 and MdmX resulted in the identification of a water molecule with a long residence time that appears to be modulated by the conformation of Y100/99. These observations lead us to speculate that dual inhibitors either i) stabilize both Mdm2 and MdmX with Y100/99 in the open conformation typically seen in complexes of Mdm2 with p53, or ii) the dual inhibitors are agnostic to the conformation of Y100/99...
April 20, 2017: Proteins
https://www.readbyqxmd.com/read/28414026/targeting-oct2-and-p53-formononetin-prevents-cisplatin-induced-acute-kidney-injury
#5
Di Huang, Chuangyuan Wang, Yingjie Duan, Qiang Meng, Zhihao Liu, Xiaokui Huo, Huijun Sun, Xiaodong Ma, Kexin Liu
Nephrotoxicity is one of major side effects of cisplatin in chemotherapy. Therefore, there is an urgent medical need to develop drugs that may protect kidney from toxicity. In previous study, we found that it showed the protective effects of formononetin against apoptosis by upregulating Nrf2. In this study, we investigated the renoprotective effect of formononetin against cisplatin-induced AKI and tried to elucidate the possible mechanisms. The amelioration of renal function, histopathological changes, and apoptosis in tubular cells was observed after formononetin treatment...
July 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28387455/fast-nmr-based-determination-of-the-3d-structure-of-the-binding-site-of-protein-ligand-complexes-with-weak-affinity-binders
#6
Marielle A Wälti, Roland Riek, Julien Orts
In early drug discovery approaches, screening hits are often weak affinity binders that are difficult to characterize in structural detail, particularly towards obtaining the 3D structure of protein-ligand complexes at atomic resolution. NMR is the outstanding technique to tackle such problems, yet suffers from a tedious structure calculation process. NMR(2) was recently developed to alleviate the laborious element of routine NMR structure calculation procedures and provides the structural information at protein-ligand interaction sites orders of magnitude faster than standard procedures...
May 2, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28351017/performance-of-a-docking-molecular-dynamics-protocol-for-virtual-screening-of-nutlin-class-inhibitors-of-mdmx
#7
Nagakumar Bharatham, Kristin E Finch, Jaeki Min, Anand Mayasundari, Michael A Dyer, R Kiplin Guy, Donald Bashford
A virtual screening protocol involving docking and molecular dynamics has been tested against the results of fluorescence polarization assays testing the potency of a series of compounds of the nutlin class for inhibition of the interaction between p53 and Mdmx, an interaction identified as a driver of certain cancers. The protocol uses a standard docking method (AutoDock) with a cutoff based on the AutoDock score (ADscore), followed by molecular dynamics simulation with a cutoff based on root-mean-square-deviation (RMSD) from the docked pose...
February 24, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28340577/gene-and-protein-analysis-reveals-that-p53-pathway-is-functionally-inactivated-in-cytogenetically-normal-acute-myeloid-leukemia-and-acute-promyelocytic-leukemia
#8
Julia Abramowitz, Tzahi Neuman, Riki Perlman, Dina Ben-Yehuda
BACKGROUND: Mechanisms that inactivate the p53 pathway in Acute Myeloid Leukemia (AML), other than rare mutations, are still not well understood. METHODS: We performed a bioinformatics study of the p53 pathway function at the gene expression level on our collection of 1153 p53-pathway related genes. Publically available Affymetrix data of 607 de-novo AML patients at diagnosis were analyzed according to the patients cytogenetic, FAB and molecular mutations subtypes...
March 24, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/28337384/topoisomerase-i-top1-a-major-target-of-fl118-for-its-antitumor-efficacy-or-mainly-involved-in-its-side-effects-of-hematopoietic-toxicity
#9
EDITORIAL
Fengzhi Li, Xiang Ling, Danni L Harris, Jianqun Liao, Yuping Wang, David Westover, Guohui Jiang, Bo Xu, Patrick M Boland, Chunyang Jin
FL118 is a novel camptothecin (CPT) analogue that possesses exceptional antitumor efficacy in human tumor animal models. To date, two CPT analogues, irinotecan and topotecan, have been approved by the FDA for cancer treatment. FL118 exhibits superior antitumor activity over irinotecan and topotecan, and effectively overcomes the irinotecan- or topotecan-resistant human tumors in animal models. Accordingly, FL118 selectively inhibits the expression of multiple cancer-associated proteins (survivin, Mcl-1, XIAP, cIAP2, MdmX)...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28296148/dimp53-1-a-novel-small-molecule-dual-inhibitor-of-p53-mdm2-x-interactions-with-multifunctional-p53-dependent-anticancer-properties
#10
Joana Soares, Margarida Espadinha, Liliana Raimundo, Helena Ramos, Ana Sara Gomes, Sara Gomes, Joana B Loureiro, Alberto Inga, Flávio Reis, Célia Gomes, Maria M M Santos, Lucília Saraiva
The transcription factor p53 plays a crucial role in cancer development and dissemination, and thus, p53-targeted therapies are among the most encouraging anticancer strategies. In human cancers with wild-type (wt) p53, its inactivation by interaction with murine double minute (MDM)2 and MDMX is a common event. Simultaneous inhibition of the p53 interaction with both MDMs is crucial to restore the tumor suppressor activity of p53. Here, we describe the synthesis of the new tryptophanol-derived oxazoloisoindolinone DIMP53-1 and identify its activity as a dual inhibitor of the p53-MDM2/X interactions using a yeast-based assay...
March 10, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28281901/tp53-and-its-potential-therapeutic-role-as-a-target-in-bladder-cancer
#11
Chiara Ciccarese, Francesco Massari, Ana Blanca, Giampaolo Tortora, Rodolfo Montironi, Liang Cheng, Marina Scarpelli, Maria R Raspollini, Nuno Vau, Jorge Fonseca, Antonio Lopez-Beltran
Despite more than 30 years of research on p53 resulting in >50,000 publications, we are now beginning to figure out the complexity of the p53 pathway, gene ontology and conformational structure of the molecule. Recent years brought great advances in p53 related drugs and the potencial ways in which p53 is inactivated in cancer. Areas covered: We searched for related publications on Pubmed and ClinicalTrial.gov using the following keywords 'p53, Tp53, p53 and bladder cancer, p53 and therapeutic target'. Relevant articles improved the understanding on p53 pathways and their potential as candidate to targeted therapy in bladder cancer...
April 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28126523/positive-effect-of-mdm2-on-p53-expression-explains-excitability-of-p53-in-response-to-dna-damage
#12
Ján Eliaš
Most of the existing biological models consider Mdm2 as a dominant negative regulator of p53 appearing in several negative feedback loops. However, in addition to targeting p53 for degradation, Mdm2 in tight cooperation with MdmX can control expression levels of p53 through enhanced induction of p53 synthesis in response to DNA damage. Whilst ATM-dependent phosphorylation of p53 is not observed to be important in this enhanced synthesis, ATM-dependent phosphorylation of Mdm2 (as well as MdmX) is essential for its dual role, which is accompanied with widely oscillating p53...
April 7, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28118981/monitoring-p53-by-mdm2-and-mdmx-is-required-for-endocrine-pancreas-development-and-function-in-a-spatio-temporal-manner
#13
Yiwei Zhang, Shelya X Zeng, Qian Hao, Hua Lu
Although p53 is not essential for normal embryonic development, it plays a pivotal role in many biological and pathological processes, including cell fate determination-dependent and independent events and diseases. The expression and activity of p53 largely depend on its two biological inhibitors, MDM2 and MDMX, which have been shown to form a complex in order to tightly control p53 to an undetectable level during early stages of embryonic development. However, more delicate studies using conditional gene-modification mouse models show that MDM2 and MDMX may function separately or synergistically on p53 regulation during later stages of embryonic development and adulthood in a cell and tissue-specific manner...
March 1, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28096294/mouse-modelling-of-the-mdm2-mdmx-p53-signalling-axis
#14
Nicole R Tackmann, Yanping Zhang
It is evident that p53 activity is critical for tumour prevention and stress response through its transcriptional activation of genes affecting cellular senescence, apoptosis, cellular metabolism, and DNA repair. The regulation of p53 is highly complex, and MDM2 and MDMX are thought to be critical for deciding the fate of p53, both through inhibitory binding and post-translational modification. Many mouse models have been generated to study the regulation of p53 in vivo, and they have altered our interpretations of how p53 is regulated by MDM2 and MDMX...
February 1, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28077607/anatomy-of-mdm2-and-mdm4-in-evolution
#15
Ban Xiong Tan, Hoe Peng Liew, Joy S Chua, Farid J Ghadessy, Yaw Sing Tan, David P Lane, Cynthia R Coffill
Mouse double minute (Mdm) genes span an evolutionary timeframe from the ancient eukaryotic placozoa Trichoplax adhaerens to Homo sapiens, implying a significant and possibly conserved cellular role throughout history. Maintenance of DNA integrity and response to DNA damage involve many key regulatory pathways, including precise control over the tumour suppressor protein p53. In most vertebrates, degradation of p53 through proteasomal targeting is primarily mediated by heterodimers of Mdm2 and the Mdm2-related protein Mdm4 (also known as MdmX)...
February 1, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28069666/negative-auto-regulators-trap-p53-in-their-web
#16
Xiang Zhou, Bo Cao, Hua Lu
The transcriptional factor p53 activates the expression of a myriad of target genes involving a complicated signalling network, resulting in various cellular outcomes, such as growth arrest, senescence, apoptosis, and metabolic changes, and leading to consequent suppression of tumour growth and progression. Because of the profoundly adverse effect of p53 on growth and proliferation of cancer cells, several feedback mechanisms have been employed by the cells to constrain p53 activity. Two major antagonists MDM2 and MDMX (the long forms) are transcriptionally induced by p53, but in return block p53 activity, forming a negative feedback circuit and rendering chemoresistance of several cancer cells...
February 1, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28050229/dual-function-of-mdm2-and-mdmx-toward-the-tumor-suppressors-p53-and-rb
#17
REVIEW
Jesús Hernández-Monge, Adriana Berenice Rousset-Roman, Ixaura Medina-Medina, Vanesa Olivares-Illana
The orchestrated crosstalk between the retinoblastoma (RB) and p53 pathways contributes to preserving proper homeostasis within the cell. The deregulation of one or both pathways is a common factor in the development of most types of human cancer. The proto-oncoproteins MDMX and MDM2 are the main regulators of the well- known tumor suppressor p53 protein. Under normal conditions, MDM2 and MDMX inhibit p53, either via repression of its transcriptional activity by protein-protein interaction, or via polyubiquitination as a result of MDM2-E3 ubiquitin ligase activity, for which MDM2 needs to dimerize with MDMX...
September 2016: Genes & Cancer
https://www.readbyqxmd.com/read/28048940/toward-understanding-the-molecular-recognition-of-albumin-by-p53-activating-stapled-peptide-atsp-7041
#18
Garima Tiwari, Chandra S Verma
Reactivation of tumor-suppressing activity of p53 protein by targeting its negative regulator MDM2/MDMX has been pursued as a potential anticancer strategy. A promising dual inhibitor of MDM2/MDMX that has been developed and is currently in clinical trials is the stapled peptide ATSP-7041. The activity of this molecule is reported to be modulated in the presence of serum. Albumin is the most abundant protein in serum and is known to bind reversibly to several molecules. To study this interaction, we develop a protocol combining molecular modeling, docking, and simulations...
January 20, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28042966/computed-binding-of-peptides-to-proteins-with-meld-accelerated-molecular-dynamics
#19
Joseph A Morrone, Alberto Perez, Justin MacCallum, Ken A Dill
It has been a challenge to compute the poses and affinities for binding of peptides to proteins by molecular dynamics (MD) simulations. Such computations would be valuable for capturing the physics and the conformational freedom of the molecules, but they are currently too computationally expensive. Here we describe using MELD (Modeling Employing Limited Data)-accelerated MD for finding the binding poses and approximate relative binding free energies for flexible-peptide/protein interactions. MELD uses only weak information about the binding motif and not the detailed binding mode that is typically required by other free-energy-based methods...
January 19, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28042965/molecular-simulations-identify-binding-poses-and-approximate-affinities-of-stapled-%C3%AE-helical-peptides-to-mdm2-and-mdmx
#20
Joseph A Morrone, Alberto Perez, Qiaolin Deng, Sookhee N Ha, M Katharine Holloway, Tomi K Sawyer, Bradley S Sherborne, Frank K Brown, Ken A Dill
Traditionally, computing the binding affinities of proteins to even relatively small and rigid ligands by free-energy methods has been challenging due to large computational costs and significant errors. Here, we apply a new molecular simulation acceleration method called MELD (Modeling by Employing Limited Data) to study the binding of stapled α-helical peptides to the MDM2 and MDMX proteins. We employ free-energy-based molecular dynamics simulations (MELD-MD) to identify binding poses and calculate binding affinities...
January 19, 2017: Journal of Chemical Theory and Computation
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