Abstract:
:Methods to accurately predict potential drug target mutations in response to early-stage leads could drive the design of more resilient first generation drug candidates. In this study, a structure-based protein design algorithm (K* in the OSPREY suite) was used to prospectively identify single-nucleotide polymorphisms that confer resistance to an experimental inhibitor effective against dihydrofolate reductase (DHFR) from Staphylococcus aureus. Four of the top-ranked mutations in DHFR were found to be catalytically competent and resistant to the inhibitor. Selection of resistant bacteria in vitro reveals that two of the predicted mutations arise in the background of a compensatory mutation. Using enzyme kinetics, microbiology, and crystal structures of the complexes, we determined the fitness of the mutant enzymes and strains, the structural basis of resistance, and the compensatory relationship of the mutations. To our knowledge, this work illustrates the first application of protein design algorithms to prospectively predict viable resistance mutations that arise in bacteria under antibiotic pressure.
journal_name
Proc Natl Acad Sci U S Aauthors
Reeve SM,Gainza P,Frey KM,Georgiev I,Donald BR,Anderson ACdoi
10.1073/pnas.1411548112subject
Has Abstractpub_date
2015-01-20 00:00:00pages
749-54issue
3eissn
0027-8424issn
1091-6490pii
1411548112journal_volume
112pub_type
杂志文章abstract::We describe retroviral expression vectors containing cDNAs encoding part of fibronectin preceded by the signal and "pro" sequences of parathyroid hormone. The recombinant retroviruses were used to generate NIH 3T3 cell lines stably producing functionally active fragments of fibronectin. The recombinant fibronectins (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.84.3.754
更新日期:1987-02-01 00:00:00
abstract::Outer membrane protein (OMP) biogenesis is critical to bacterial physiology because the cellular envelope is vital to bacterial pathogenesis and antibiotic resistance. The process of OMP biogenesis has been studied in vivo, and each of its components has been studied in isolation in vitro. This work integrates paramet...
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.1601002113
更新日期:2016-08-16 00:00:00
abstract::Chick-limb mesodermal cells have been maintained in tissue culture under conditions that permit development of muscle and cartilage. 3-Acetylpyridine, a nicotinamide-antagonized muscle teratogen, potentiates chondrogenic expression in cell cultures, as evidenced by histological and biochemical criteria, including the ...
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.70.6.1713
更新日期:1973-06-01 00:00:00
abstract::Dendritic cell (DC) lectins mediate the recognition, uptake, and processing of antigens, but they can also be coopted by pathogens for infection. These distinct activities depend upon the routing of antigens within the cell. Antigens directed to endosomal compartments are degraded, and the peptides are presented on ma...
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.1820165116
更新日期:2019-07-23 00:00:00
abstract::The recognition of carrier proteins by multiple catalytic partners occurs in every cycle of chain elongation in the biosynthesis of fatty acids and of the pharmacologically important polyketide and nonribosomal peptide natural products. To dissect the features of carrier proteins that determine specific recognition at...
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.0705122104
更新日期:2007-07-10 00:00:00
abstract::A detailed phenomenology of low energy excitations is a crucial starting point for microscopic understanding of complex materials, such as the cuprate high-temperature superconductors. Because of its unique momentum-space discrimination, angle-resolved photoemission spectroscopy (ARPES) is ideally suited for this task...
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.1209471109
更新日期:2012-11-06 00:00:00
abstract::The cycles of carbon and oxygen at the Earth surface are intimately linked, where the burial of organic carbon into sediments represents a source of oxygen to the surface environment. This coupling is typically quantified through the isotope records of organic and inorganic carbon. Yet, the late Neoproterozoic Eon, th...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 历史文章,杂志文章
doi:10.1073/pnas.1101755108
更新日期:2011-04-05 00:00:00
abstract::The MAL6 locus is one of five closely related unlinked loci, any one of which is sufficient for fermentation of maltose in Saccharomyces. Previous genetic analysis indicated that this locus is defined by two complementation groups, MALp and MALg. MALp reportedly is a regulatory gene required for inducible synthesis of...
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.81.9.2811
更新日期:1984-05-01 00:00:00
abstract::Because of the rise in atmospheric oxygen 2.3 billion years ago (Gya) and the subsequent changes in oceanic redox state over the last 2.3-1 Gya, trace metal bioavailability in marine environments has changed dramatically. Although theorized to have influenced the biological usage of metals leaving discernable genomic ...
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.0605798103
更新日期:2006-11-21 00:00:00
abstract::We have constructed 26-amino acid transmembrane proteins that specifically transform cells but consist of only two different amino acids. Most proteins are long polymers of amino acids with 20 or more chemically distinct side-chains. The artificial transmembrane proteins reported here are the simplest known proteins w...
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.1514230112
更新日期:2015-08-25 00:00:00
abstract::Exposing primary cultures of cerebellar granule neurons to 100 nM phorbol 12-myristate 13-acetate (PMA) for 24 hr decreases the Ca2+/phosphatidylserine/diolein-dependent protein kinase C (PKC; ATP:protein phosphotransferase, EC 2.7.1.37) by approximately 90% in the 100,000 x g supernatant and pellet fractions of neuro...
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.87.5.1983
更新日期:1990-03-01 00:00:00
abstract::Synthetic pheomelanins from enzymic oxidation of the 3,4-dihydroxyphenylalanine (dopa) derivative 5-S-cysteinyldopa have been examined by ESR spectroscopy. These alkalisoluble polymers contain a novel kind of free radical that is spectroscopically distinct from that found in eumelanins. Delocalization of the unpaired ...
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.79.9.2885
更新日期:1982-05-01 00:00:00
abstract::Mapping biological pathways across microbial genomes is a highly important technique in functional studies of biological systems. Existing methods mainly rely on sequence-based orthologous gene mapping, which often leads to suboptimal mapping results because sequence-similarity information alone does not contain suffi...
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.0509737102
更新日期:2006-01-03 00:00:00
abstract::Expression of the homeobox protein CDX1 is lost or reduced in a significant proportion of colorectal carcinomas (CRCs) but the underlying mechanism for this is unclear. We have demonstrated absence of CDX1 mRNA expression in 7 of 37 CRC cell lines and shown that all 7 cell lines have a methylated CDX1 promoter. Twenty...
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.0307190101
更新日期:2004-01-13 00:00:00
abstract::We have examined whether dissociation of the histone octamer is required for elongation of RNA transcripts through arrays of nucleosome cores in vitro. Control or dimethyl suberimidate-crosslinked histone octamers were reconstituted onto supercoiled, closed circular pT207-18 DNA, which contains tandemly repeated 207-b...
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.90.13.6203
更新日期:1993-07-01 00:00:00
abstract::The progesterone receptor (PGR) is a ligand-activated transcription factor with key roles in the regulation of female fertility. Much has been learned of the actions of PGR signaling through the use of pharmacologic inhibitors and genetic manipulation, using mouse mutagenesis. Characterization of rats with a null muta...
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.1601825113
更新日期:2016-04-12 00:00:00
abstract::Tissue cultures of Actinidia kolomikta can be maintained as callus through repeated passages on a nutrient medium devoid of cytokinin but containing inorganic nutrients, sucrose, and other basal organics plus auxin. Under these conditions, actively growing callus contained 2 and 0.5 nmol of the cytokinins zeatin [io(6...
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.83.4.972
更新日期:1986-02-01 00:00:00
abstract::Osteocalcin, a bone-specific protein and marker of the mature osteoblast, is expressed only in nonproliferating osteoblasts in a mineralizing extracellular matrix, while type I collagen is expressed in proliferating cells. The nuclear proteins encoded by the c-fos and c-jun protooncogenes are expressed during the prol...
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.87.24.9990
更新日期:1990-12-01 00:00:00
abstract::The v-jun oncogene encodes a nuclear DNA binding protein that functions as a transcription factor and is part of the activator protein 1 complex. Oncogenic transformation by v-jun is thought to be mediated by the aberrant expression of specific target genes. To identify such Jun-regulated genes and to explore the mech...
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.94.23.12396
更新日期:1997-11-11 00:00:00
abstract::Theories of evolution that state natural selection acts on individuals have been modified to include multiple levels of selection. Here we demonstrate in chimeric protochordates that primitive germ cell (pgc) and somatic cell (psc) lineages have traits that also make them likely units of natural selection. Specificall...
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.96.16.9148
更新日期:1999-08-03 00:00:00
abstract::Current issues pertaining to theoretical simulations of materials, with a focus on systems of nanometer-scale dimensions, are discussed. The use of atomistic simulations as high-resolution numerical experiments, enabling and guiding formulation and testing of analytic theoretical descriptions, is demonstrated through ...
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.0408038102
更新日期:2005-05-10 00:00:00
abstract::Biological organisms have evolved a wide range of immune mechanisms to defend themselves against pathogens. Beyond molecular details, these mechanisms differ in how protection is acquired, processed, and passed on to subsequent generations-differences that may be essential to long-term survival. Here, we introduce a m...
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.1600663113
更新日期:2016-08-02 00:00:00
abstract::We study atomic models of the thermodynamics of the structural transition of peptides that form alpha-helices. The effect of sequence variation on alpha-helix formation for alanine-rich peptides, Ac-Ala21-methyl amide (A21) and Ac-A5 (AAARA)3A-methyl amide (Fs peptide), is investigated by atomic simulation studies of ...
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.042496899
更新日期:2002-03-05 00:00:00
abstract::The DNA sequences of wheat Acc-1 and Acc-2 loci, encoding the plastid and cytosolic forms of the enzyme acetyl-CoA carboxylase, were analyzed with a view to understanding the evolution of these genes and the origin of the three genomes in modern hexaploid wheat. Acc-1 and Acc-2 loci from each of the wheats Triticum ur...
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.0803981105
更新日期:2008-07-15 00:00:00
abstract::Granulocyte-colony-stimulating factor (G-CSF) stimulates the proliferation and differentiation of cells of the neutrophil lineage by interaction with a specific receptor. Early signal transduction events following G-CSF receptor activation were studied. We detected tyrosine phosphorylation of both the G-CSF receptor a...
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.91.8.2985
更新日期:1994-04-12 00:00:00
abstract::Drosophila melanogaster CRYPTOCHROME (CRY) mediates behavioral and electrophysiological responses to blue light coded by circadian and arousal neurons. However, spectroscopic and biochemical assays of heterologously expressed CRY suggest that CRY may mediate functional responses to UV-A (ultraviolet A) light as well. ...
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.1607989114
更新日期:2017-01-24 00:00:00
abstract::Surface Ig (sIg) of follicular lymphoma (FL) is vital for tumor cell survival. We found previously that the Ig in FL is unusual, because the variable region genes carry sequence motifs for N-glycan addition. These are introduced by somatic mutation and are tumor specific. Unexpectedly, added glycans terminate at high ...
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.1009388107
更新日期:2010-10-26 00:00:00
abstract::Let E and F be vector bundles and D:E --> F an operator of order k. We associate a sequence of invariants ((l))(D), l >/= 0 with D which generalize the concept of curvature in a natural way. In the case where D = D(theta) is the differential operator of a connection theta on a vector bundle E, ((1))(D(theta)) is the c...
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.70.3.797
更新日期:1973-03-01 00:00:00
abstract::Given the widely noted increase in the warming effects of rising greenhouse gas concentrations, it has been unclear why global surface temperatures did not rise between 1998 and 2008. We find that this hiatus in warming coincides with a period of little increase in the sum of anthropogenic and natural forcings. Declin...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 历史文章,杂志文章
doi:10.1073/pnas.1102467108
更新日期:2011-07-19 00:00:00
abstract::We report on the location of the chain part of the retinylidene chromophore in the projected density of bacteriorhodopsin as determined by neutron diffraction from the two-dimensional purple membrane lattice. For this purpose, partially deuterated retinal was synthesized containing 10 deuterons at positions C-8, C-10,...
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.82.10.3227
更新日期:1985-05-01 00:00:00