Abstract：
:Large-scale conformational changes in proteins are often associated with the binding of a substrate. Because conformational changes may be related to the function of an enzyme, understanding the kinetics and energetics of these motions is very important. We have delineated the atomically detailed conformational transition pathway of the phosphotransferase enzyme adenylate kinase (AdK) in the absence and presence of an inhibitor. The computed free energy profiles associated with conformational transitions offer detailed mechanistic insights into, as well as kinetic information on, the ligand binding mechanism. Specifically, potential of mean force calculations reveal that in the ligand-free state, there is no significant barrier separating the open and closed conformations of AdK. The enzyme samples near closed conformations, even in the absence of its substrate. The ligand binding event occurs late, toward the closed state, and transforms the free energy landscape. In the ligand-bound state, the closed conformation is energetically most favored with a large barrier to opening. These results emphasize the underlying dynamic nature of the enzyme and indicate that the conformational transitions in AdK are more intricate than a mere two-state jump between the crystal-bound and -unbound states. Based on the existence of the multiple conformations of the enzyme in the open and closed states, a different viewpoint of ligand binding is presented. Our estimated activation energy barrier for the conformational transition is also in reasonable accord with the experimental findings.
journal_name
Proc Natl Acad Sci U S Aauthors
Arora K,Brooks CL 3rddoi
10.1073/pnas.0706443104subject
Has Abstractpub_date
2007-11-20 00:00:00pages
18496-501issue
47eissn
0027-8424issn
1091-6490pii
0706443104journal_volume
104pub_type
杂志文章abstract：:In this study, we quantified 249 mature micro-RNA (miRNA) transcripts in estrogen receptor-positive (ER(+)) primary breast tumors of patients with lymph node-negative (LNN) disease to identify miRNAs associated with metastatic capability. In addition, the prognostic value of the candidate miRNAs was determined in ER(-...
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.0803304105
更新日期：2008-09-02 00:00:00
abstract：:Saccharomyces cerevisiae strain PP5 has a phosphodiesterase (PDE) deficiency that results in heat-shock sensitivity due to the intracellular accumulation of cAMP. This strain also carries the cam mutation, which confers permeability to cAMP and, as shown here, to other compounds. Expression of rat type IV PDE in these...
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.90.24.11970
更新日期：1993-12-15 00:00:00
abstract：:Untargeted metabolomics of environmental samples routinely detects thousands of small molecules, the vast majority of which cannot be identified. Meta-mass shift chemical (MeMSChem) profiling was developed to identify mass differences between related molecules using molecular networks. This approach illuminates metabo...
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.1710248114
更新日期：2017-10-31 00:00:00
abstract：:Treatment of full-thickness damage to hyaline cartilage is hampered by the limited availability of autologous healthy cartilage and the lengthy, cost-prohibitive cell isolation and expansion steps associated with autologous cartilage implantation (ACI). Here we report a strategy for de novo engineering of ectopic auto...
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.0907774107
更新日期：2010-02-23 00:00:00
abstract：:Nuclear factor of activated T cells (NFAT) proteins are Ca(2+)-regulated transcription factors that control gene expression in many cell types. NFAT proteins are heavily phosphorylated and reside in the cytoplasm of resting cells; when cells are stimulated by a rise in intracellular Ca(2+), NFAT proteins are dephospho...
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.1019711108
更新日期：2011-07-12 00:00:00
abstract：:The p6 domain of HIV-1 Gag contains highly conserved peptide motifs that recruit host machinery to sites of virus assembly, thereby promoting particle release from the infected cell. We previously reported that mutations in the YPXnL motif of p6, which binds the host protein Alix, severely impair HIV-1 replication. Pr...
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.1820333116
更新日期：2019-04-30 00:00:00
abstract：:Cells contain numerous enzymes that use molecular oxygen for their reactions. Often, their active sites are buried deeply inside the protein, which raises the question whether there are specific access channels guiding oxygen to the site of catalysis. Choosing 12/15-lipoxygenase as a typical example for such oxygen-de...
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.0702401104
更新日期：2007-08-14 00:00:00
abstract：:A single animal group can display different types of collective motion at different times. For a one-dimensional individual-based model of self-organizing group formation, we show that repeated switching between distinct ordered collective states can occur entirely because of stochastic effects. We introduce a framewo...
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.0608270104
更新日期：2007-04-03 00:00:00
abstract：:A "projection function," P(x,z), is defined as the partial integral of the molecular electron density, rho(x,y,z), over the region -infinity < y < +infinity. The projection provides a three-dimensional representation of molecular electron distributions. Chemically useful information can be discerned from graphical dis...
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.76.6.2499
更新日期：1979-06-01 00:00:00
abstract：:We have isolated, cloned, and expressed a male antennae-specific pheromone-degrading enzyme (PDE) [Antheraea polyphemus PDE (ApolPDE), formerly known as Sensillar Esterase] from the wild silkmoth, A. polyphemus, which seems essential for the rapid inactivation of pheromone during flight. The onset of enzymatic activit...
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.0505340102
更新日期：2005-09-27 00:00:00
abstract：:Salmonella enterica serovar Typhi can colonize the gallbladder and persist in an asymptomatic carrier state that is frequently associated with the presence of gallstones. We have shown that salmonellae form bile-mediated biofilms on human gallstones and cholesterol-coated surfaces in vitro. Here, we test the hypothesi...
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.1000862107
更新日期：2010-03-02 00:00:00
abstract：:Kdo (3-deoxy-d-manno-oct-2-ulosonic acid) is an eight-carbon sugar mostly confined to Gram-negative bacteria. It is often involved in attaching surface polysaccharides to their lipid anchors. α-Kdo provides a bridge between lipid A and the core oligosaccharide in all bacterial LPSs, whereas an oligosaccharide of β-Kdo...
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.1603146113
更新日期：2016-05-31 00:00:00
abstract：:The bacterio-opsin gene was introduced into a "blind" Halobacterium salinarium mutant that (i) lacked all the four retinal proteins [bacteriorhodopsin (BR), halorhodopsin, and sensory rhodopsins (SRs) I and II] and the transducer protein for SRI and (ii) showed neither attractant response to long wavelength light nor ...
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.90.20.9446
更新日期：1993-10-15 00:00:00
abstract：:We used 5,6-dichloro-beta D-ribofuranosyl-benzimidazole (DRB), a selective and reversible inhibitor of mRNA production, to investigate the regulation of the pathway leading to resistance to viruses in cells treated with interferon (IF). DRB allows initiation of transcription but promotes premature termination of the n...
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.77.1.452
更新日期：1980-01-01 00:00:00
abstract：:Xenopus laevis oocytes were injected with poly(A)+-mRNA isolated from chorionating follicular epithelium of the domesticated silk moth (Bombyx mori). On two-dimensional gel electrophoresis, the resultant translation products comigrated with authentic, secreted, chorion standards, demonstrating that the frog oocyte sys...
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.79.4.1032
更新日期：1982-02-01 00:00:00
abstract：:The Raf-1 serine/threonine kinase is a key protein involved in the transmission of many growth and developmental signals. In this report, we show that autoinhibition mediated by the noncatalytic, N-terminal regulatory region of Raf-1 is an important mechanism regulating Raf-1 function. The inhibition of the regulatory...
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.95.16.9214
更新日期：1998-08-04 00:00:00
abstract：:The distribution of dopamine-containing processes in the striatum of fetal and neonatal cats was studied by immunohistochemical and glyoxylic acid histofluorescence methods and compared to the distribution of acetylcholinesterase (acetylcholine acetylhydrolase, EC 3.1.1.7) observed by thiocholine histochemistry in 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.78.9.5871
更新日期：1981-09-01 00:00:00
abstract：:Gonadotropin-releasing hormone (GnRH) is important in reproduction, although the mechanism of central hypogonadism in humans remains unclear. Because the GnRH neuron originates from the olfactory placode and migrates to the hypothalamus during development, central hypogonadism in humans could be caused by failure in n...
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.88.8.3402
更新日期：1991-04-15 00:00:00
abstract：:The lactate racemase enzyme (LarA) of Lactobacillus plantarum harbors a (SCS)Ni(II) pincer complex derived from nicotinic acid. Synthesis of the enzyme-bound cofactor requires LarB, LarC, and LarE, which are widely distributed in microorganisms. The functions of the accessory proteins are unknown, but the LarB C termi...
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.1600486113
更新日期：2016-05-17 00:00:00
abstract：:The betaalpha barrel is the common protein fold of numerous enzymes and was proposed recently to be the result of gene duplication and fusion of an ancient half-barrel. The initial enzyme of shikimate biosynthesis possesses the additional feature of feedback regulation. The crystal structure and kinetic studies on chi...
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.0337566100
更新日期：2003-02-04 00:00:00
abstract：:Methane emissions due to accidents in the oil and natural gas sector are very challenging to monitor, and hence are seldom considered in emission inventories and reporting. One of the main reasons is the lack of measurements during such events. Here we report the detection of large methane emissions from a gas well bl...
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.1908712116
更新日期：2019-12-16 00:00:00
abstract：:Alcohol exposure during development can cause brain malformations and neurobehavioral abnormalities. In view of the teratogenicity of ethanol, identification of molecules that could counteract the neurotoxic effects of alcohol deserves high priority. Here, we report that pituitary adenylate cyclase-activating polypept...
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.082112699
更新日期：2002-04-30 00:00:00
abstract：:Previous studies have failed to detect an interaction between monomeric soluble CD4 (sCD4) and class II major histocompatibility complex (MHC) proteins, suggesting that oligomerization of CD4 on the cell surface may be required to form a stable class II MHC binding site. To test this possibility, we transfected the F4...
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.92.14.6444
更新日期：1995-07-03 00:00:00
abstract：:Hitherto it has not been possible to obtain spore and stalk cell differentiation of the cellular slime molds in submerged cultures. It is shown here that cells, when placed in roller tubes under an atmosphere of oxygen, will form clumps and differentiate in 48-72 hr into mature spores and stalk cells. Although differe...
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.74.1.268
更新日期：1977-01-01 00:00:00
abstract：:When encountering unexpected event changes, memories of relevant past experiences must be updated to form new representations. Current models of memory updating propose that people must first generate memory-based predictions to detect and register that features of the environment have changed, then encode the new eve...
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.1918063117
更新日期：2020-11-24 00:00:00
abstract：:The classic anthropological hypothesis known as the "obstetrical dilemma" is a well-known explanation for human altriciality, a condition that has significant implications for human social and behavioral evolution. The hypothesis holds that antagonistic selection for a large neonatal brain and a narrow, bipedal-adapte...
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.1205282109
更新日期：2012-09-18 00:00:00
abstract：:The commitment of differentiating cells to a specialized fate is fundamental to the correct assembly of tissues within a multicellular organism. Because commitment is often irreversible, entry into and progression through this phase of development must be tightly regulated. Under nitrogen-limiting conditions, the mult...
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.1610533113
更新日期：2016-11-08 00:00:00
abstract：:Transitions in dealing with the root causes of environmental problems are advocated to achieve environmental sustainability. These transformations include (i) a demographic transition, (ii) a technology transition that includes the "green" automobile, (iii) an economic transition to one in which prices reflect full en...
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.89.3.870
更新日期：1992-02-01 00:00:00
abstract：:In vitro recombination of cloned H-2 genes resulted in two allogeneically novel mouse transplantation antigens in which the C2 domains of H-2Ld and H-2Dd were exchanged. These genes were introduced into mouse L cells by DNA-mediated gene transfer. We have used these transformed fibroblast lines, expressing recombinant...
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.80.7.2040
更新日期：1983-04-01 00:00:00
abstract：:The most frequent form of inherited amyloidoses is associated with mutations in the transthyretin (TTR) gene coding for 127-amino acid residues of four identical, noncovalently linked subunits that form a pair of dimers in the plasma protein complex. Amyloid fibrils containing the variant and to a lesser extent the wi...
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.93.13.6302
更新日期：1996-06-25 00:00:00
