Abstract:
:Conformationally compromised oncogenic mutants of the tumor suppressor protein p53 can, in principle, be rescued by small molecules that bind the native, but not the denatured state. We describe a strategy for the rational search for such molecules. A nine-residue peptide, CDB3, which was derived from a p53 binding protein, binds to p53 core domain and stabilizes it in vitro. NMR studies showed that CDB3 bound to p53 at the edge of the DNA binding site, partly overlapping it. The fluorescein-labeled peptide, FL-CDB3, binds wild-type p53 core domain with a dissociation constant of 0.5 microM, and raises the apparent melting temperatures of wild-type and a representative oncogenic mutant, R249S core domain. gadd45 DNA competes with CDB3 and displaces it from its binding site. But this competition does not preclude CDB3 from being a lead compound. CDB3 may act as a "chaperone" that maintains existing or newly synthesized destabilized p53 mutants in a native conformation and then allows transfer to specific DNA, which binds more tightly. Indeed, CDB3 restored specific DNA binding activity to a highly destabilized mutant I195T to close to that of wild-type level.
journal_name
Proc Natl Acad Sci U S Aauthors
Friedler A,Hansson LO,Veprintsev DB,Freund SM,Rippin TM,Nikolova PV,Proctor MR,Rüdiger S,Fersht ARdoi
10.1073/pnas.241629998keywords:
subject
Has Abstractpub_date
2002-01-22 00:00:00pages
937-42issue
2eissn
0027-8424issn
1091-6490pii
241629998journal_volume
99pub_type
杂志文章abstract::NIH 3T3 mouse cells were transfected with plasmids that induce efficient expression of either (i) the Rous sarcoma virus v-src gene, (ii) the chicken c-src gene, or (iii) a recombinant gene combining the 5' portion of c-src with the 3' end of v-src. Focus formation in tissue culture and formation of large colonies in ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.81.22.7071
更新日期:1984-11-01 00:00:00
abstract::While we have come to appreciate the architectural complexity of microbially synthesized secondary metabolites, far less attention has been paid to linking their structural features with possible modes of action. This is certainly the case with tropodithietic acid (TDA), a broad-spectrum antibiotic generated by marine...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1518034113
更新日期:2016-02-09 00:00:00
abstract::Y chromosomes control essential male functions in many species, including sex determination and fertility. However, because of obstacles posed by repeat-rich heterochromatin, knowledge of Y chromosome sequences is limited to a handful of model organisms, constraining our understanding of Y biology across the tree of l...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1525164113
更新日期:2016-04-12 00:00:00
abstract::Thebaine, an intermediate of morphine biosynthesis in the poppy plant, Papaver somniferum, was transformed to oripavine, codeine, and morphine by rat liver, kidney, and brain microsomes in the presence of an NADPH-generating system. The formation of morphine, codeine, and oripavine was identified by a specific RIA, HP...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.85.4.1267
更新日期:1988-02-01 00:00:00
abstract::Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini an...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1616060114
更新日期:2017-05-16 00:00:00
abstract::Ca2+/calmodulin-dependent protein kinase enriched in cerebellar granule cells (CaM kinase Gr) is a neuronal calmodulin-dependent protein kinase whose purification and partial cloning from rat brain has been described. A combination of the polymerase chain reaction and cDNA library screening was used to determine the D...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.13.5784
更新日期:1991-07-01 00:00:00
abstract::Increased accumulation of lipofuscin in cells of the retinal pigment epithelium (RPE) is seen in several forms of macular degeneration, a common cause of blindness in humans. A major fluorophore of lipofuscin is the toxic bis-retinoid, N-retinylidene-N-retinylethanolamine (A2E). Previously, we generated mice with a kn...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.130110497
更新日期:2000-06-20 00:00:00
abstract::We have found the two-dimensional electrophoretic technique of O'Farrell to be highly efficient in the detection of charge-change substitutions in a large number of proteins. We have applied this method to determine the level of heterozygosity of the most abundant proteins in Drosophila melanogaster adults from a natu...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.76.5.2381
更新日期:1979-05-01 00:00:00
abstract::The phenotype of several erythromycin-resistant mutants of Chlamydomonas reinhardi was further characterized in terms of the electrophoretic properties of their chloroplast ribosomal proteins. In mutant ery-M2d a single protein of the large (52 S) subunit has altered properties, which probably result from a change in ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.69.12.3779
更新日期:1972-12-01 00:00:00
abstract::The potent muscarinic photoaffinity reagent N-methyl-4-piperidyl p-azidobenzilate (azido-4NMPB) was used to covalently label specific muscarinic binding sites in various brain regions and in the heart. In the cortex and hippocampus, a single specifically labeled protein with an apparent molecular mass of 86,000 dalton...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.80.1.156
更新日期:1983-01-01 00:00:00
abstract::Previous reports have shown that γδ T cells are important for the elimination of malaria parasites in humans and mice. However, how γδ T cells are involved in protective immunity against blood-stage malaria remains unknown. We infected γδ T-cell-deficient (TCRδ-KO) mice and control wild-type mice with Plasmodium bergh...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1204480109
更新日期:2012-07-24 00:00:00
abstract::Dual-color fluorescence cross-correlation spectroscopy (dual-color FCS) has previously been shown to be a suitable tool not only for binding but also for catalytic rate studies. In this work, its application as a rapid method for high-throughput screening (HTS) and evolutionary biotechnology is described. This applica...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.4.1421
更新日期:1998-02-17 00:00:00
abstract::Inteins are intervening protein sequences that undergo self-excision from a precursor protein with concomitant joining of the flanking sequences. Here, we demonstrate intein trans-splicing in Nicotiana tabacum chloroplasts by using the naturally split Ssp DnaE intein. Trans-splicing occurred whether both intein fragme...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0736538100
更新日期:2003-04-15 00:00:00
abstract::The T lineage repertoire is shaped by T cell receptor (TCR)-dependent positive and negative thymic selection processes. Using TCR-transgenic (N15tg) beta2-microglobulin-deficient (beta2m-/-) RAG-2(-/-) H-2(b) mice specific for the VSV8 (RGYVYQGL) octapeptide bound to Kb, we identified a single weak agonist peptide var...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.17.10061
更新日期:1998-08-18 00:00:00
abstract::Excessive activation of calmodulin kinase II (CaMKII) causes arrhythmias and heart failure, but the cellular mechanisms for CaMKII-targeted proteins causing disordered cell membrane excitability and myocardial dysfunction remain uncertain. Failing human cardiomyocytes exhibit increased CaMKII and voltage-gated Ca(2+) ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0913760107
更新日期:2010-03-16 00:00:00
abstract::In eukaryotes, ubiquitination is an important posttranslational process achieved through a cascade of ubiquitin-activating (E1), conjugating (E2), and ligase (E3) enzymes. Many pathogenic bacteria deliver virulence factors into the host cell that function as E3 ligases. How these bacterial "Trojan horses" integrate in...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1115025109
更新日期:2012-02-07 00:00:00
abstract::In mantle cell lymphoma (MCL), the translocation t(11;14) is considered the cytogenetic hallmark of the disease. Recently, however, deletion of the chromosomal region 11q22-q23 has been identified as a frequent event in this type of cancer, indicating the existence of a pathogenically relevant tumor suppressor gene in...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.050400997
更新日期:2000-03-14 00:00:00
abstract::A biologically active vitamin D(3) metabolite ("peak V metabolite") more polar than 25-hydroxycholecalciferol has been isolated from chicken intestines in pure form as a mono(trimethylsilyl)ether derivative. The molecule has been identified as 1,25-dihydroxycholecalciferol by means of mass spectrometry, ultraviolet ab...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.68.4.803
更新日期:1971-04-01 00:00:00
abstract::Sirtuin 2 (SIRT2) is a sirtuin family deacetylase that directs acetylome signaling, protects genome integrity, and is a murine tumor suppressor. We show that SIRT2 directs replication stress responses by regulating the activity of cyclin-dependent kinase 9 (CDK9), a protein required for recovery from replication arres...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1301463110
更新日期:2013-08-13 00:00:00
abstract::How granzymes gain entry into the cytosol of target cells during killer cell attack has been the subject of several studies in the past, but the effective delivery mechanism during target cell encounter has not been clarified. Here we show that granzyme B (GzmB) mutants lacking binding to negatively charged, essential...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0801724105
更新日期:2008-09-16 00:00:00
abstract::Genetic switches based on the [Formula: see text] system are master regulators of an array of cellular responses. Recent kinetic experiments have shown that [Formula: see text] can actively remove NF-κB bound to its genetic sites via a process called "molecular stripping." This allows the [Formula: see text] switch to...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1520483112
更新日期:2016-01-05 00:00:00
abstract::Attention to a stimulus enhances both neuronal responses and gamma frequency synchrony in visual area V4, both of which should increase the impact of attended information on downstream neurons. To determine whether gamma synchrony is common throughout the ventral stream, we recorded from neurons in the superficial and...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1011284108
更新日期:2011-07-05 00:00:00
abstract::Most evidence supports the view that ER alpha is responsible for estrogen (ovarian estradiol, E(2))-induced proliferation in the epithelial cells of the mammary gland, but despite this, proliferating epithelial cells do not express ER alpha. We have examined this apparent paradox by studying the role of ER alpha and E...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0307864100
更新日期:2004-03-16 00:00:00
abstract::As the Conus shell grows by spiraling of the outer lip around the axis, profound internal shell dissolution thins the walls of the protected penultimate whorl from several millimeters to <50mum. Shell material is added to the inside of the spire and the anterior part of the columella. The resulting shell has a uniform...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.76.7.3406
更新日期:1979-07-01 00:00:00
abstract::During vertebrate brain development, the onset of neuronal differentiation is under strict temporal control. In the mammalian thalamus and other brain regions, neurogenesis is regulated also in a spatially progressive manner referred to as a neurogenetic gradient, the underlying mechanism of which is unknown. Here we ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0910894106
更新日期:2009-11-24 00:00:00
abstract::Cholera and enterotoxigenic Escherichia coli (ETEC) are among the most common causes of acute infantile gastroenteritis globally. We previously developed a rice-based vaccine that expressed cholera toxin B subunit (MucoRice-CTB) and had the advantages of being cold chain-free and providing protection against cholera t...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0914121107
更新日期:2010-05-11 00:00:00
abstract::Most marine organisms disperse via ocean currents as larvae, so it is often assumed that larval-stage duration is the primary determinant of geographic range size. However, empirical tests of this relationship have yielded mixed results, and alternative hypotheses have rarely been considered. Here we assess the relati...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1304074110
更新日期:2013-10-08 00:00:00
abstract::The voltage-dependent gating of the colicin channel involves a substantial structural rearrangement that results in the transfer of about 35% of the 200 residues in its pore-forming domain across the membrane. This transfer appears to represent an unusual type of protein translocation that does not depend on a large, ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.022480199
更新日期:2002-02-05 00:00:00
abstract::Mutations in the DAX-1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita (AHC) critical region on the X chromosome; NR0B1] gene cause X-linked AHC associated with hypogonadotropic hypogonadism. DAX-1 encodes an unusual orphan member of the nuclear hormone receptor superfamily, acting as a transcriptional rep...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.122044099
更新日期:2002-06-11 00:00:00
abstract::Pathogenetic processes that facilitate the entry, replication, and persistence of Mycobacterium tuberculosis (MTB) in the mammalian host likely include the regulated expression of specific sets of genes at different stages of infection. Identification of genes that are differentially expressed in vivo would provide in...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.2436197100
更新日期:2003-11-25 00:00:00