Abstract:
:In enzyme catalysis, where exquisitely positioned functionality is the sine qua non, atomic coordinates for a Michaelis complex can provide powerful insights into activation of the substrate. We focus here on the initial proton transfer of the isomerization reaction catalyzed by triosephosphate isomerase and present the crystal structure of its Michaelis complex with the substrate dihydroxyacetone phosphate at near-atomic resolution. The active site is highly compact, with unusually short and bifurcated hydrogen bonds for both catalytic Glu-165 and His-95 residues. The carboxylate oxygen of the catalytic base Glu-165 is positioned in an unprecedented close interaction with the ketone and the alpha-hydroxy carbons of the substrate (C em leader O approximately 3.0 A), which is optimal for the proton transfer involving these centers. The electrophile that polarizes the substrate, His-95, has close contacts to the substrate's O1 and O2 (N em leader O < or = 3.0 and 2.6 A, respectively). The substrate is conformationally relaxed in the Michaelis complex: the phosphate group is out of the plane of the ketone group, and the hydroxy and ketone oxygen atoms are not in the cisoid configuration. The epsilon ammonium group of the electrophilic Lys-12 is within hydrogen-bonding distance of the substrate's ketone oxygen, the bridging oxygen, and a terminal phosphate's oxygen, suggesting a role for this residue in both catalysis and in controlling the flexibility of active-site loop.
journal_name
Proc Natl Acad Sci U S Aauthors
Jogl G,Rozovsky S,McDermott AE,Tong Ldoi
10.1073/pnas.0233793100keywords:
subject
Has Abstractpub_date
2003-01-07 00:00:00pages
50-5issue
1eissn
0027-8424issn
1091-6490pii
0233793100journal_volume
100pub_type
杂志文章abstract::Emerging evidence suggests that tissue plasminogen activator (tPA), currently the only FDA-approved medication for ischemic stroke, exerts important biological actions on the CNS besides its well-known thrombolytic effect. In this study, we investigated the role of tPA on primary neurons in culture and on brain recove...
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.1821979116
更新日期:2019-04-30 00:00:00
abstract::The substance P (SP)-preferring receptor neurokinin-1 receptor (NK-1R) has two forms: a full-length receptor consisting of 407 aa and a truncated receptor consisting of 311 aa. These two receptors differ in the length of the C terminus of NK-1R. We studied the undifferentiated and phorbol myristate acetate (PMA)-diffe...
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.0602563103
更新日期:2006-05-16 00:00:00
abstract::Growth of 3T3-L2 fibroblasts in medium containing 5-bromo-2'-deoxyuridine prevents the spontaneous cytodifferentiation of these cells into adipose cells. Treatment of bromodeoxyuridine-suppressed cultures at confluence with 1-methyl-3-isobutylxanthine, a promoter of the adipose conversion, results in differentiation o...
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.76.9.4451
更新日期:1979-09-01 00:00:00
abstract::We previously identified rat8 in the pathway involved in epithelial cell differentiation that occurs in the rat mammary gland at pregnancy when tubules and alveoli are formed. rat8, which encodes an IFN-inducible membrane protein, is the rat homologue of the mouse gene fragilis. By differential detergent extraction 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.0307292101
更新日期:2004-02-17 00:00:00
abstract::The origin of the multicellular animals has been investigated by rate invariant analysis of 18S rRNA sequences. These analyses indicate that (i) the Metazoa is a monophyletic taxon; (ii) the Deuterostomia is a monophyletic taxon; (iii) the Annelida-Mollusca lineage is the sister group of an arthropod subgroup; and (iv...
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.87.2.763
更新日期:1990-01-01 00:00:00
abstract::We find that histidine residues in proteins are major targets for reaction with the lipid peroxidation product 4-hydroxynon-2-enal (HNE). Reaction of insulin (which contains no sulfhydryl groups) with HNE leads to the generation of HNE-protein adducts, which are converted to radioactive derivatives upon subsequent tre...
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.89.10.4544
更新日期:1992-05-15 00:00:00
abstract::Cerebellar granule cells grown in the presence of a serum complex differentiate but are resistant to the lethal action of excitatory amino acids. When these cells are grown also in the presence of insulin-like growth factor I (IGF-I) they become fully susceptible to the toxic, lethal action of glutamate. The glutamate...
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.90.18.8752
更新日期:1993-09-15 00:00:00
abstract::Artemis gene mutations are responsible for the development of a severe combined immunodeficiency [radiation-sensitive (RS) SCID] characterized by a severe B and T cell deficiency and a normal natural killer cell population. To establish the feasibility of a gene therapy approach to the treatment of RS-SCID, we generat...
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.0608130103
更新日期:2006-10-31 00:00:00
abstract::The tumor suppressor protein p53 localizes to microtubules (MT) and, in response to DNA damage, is transported to the nucleus via the MT minus-end-directed motor protein dynein. Dynein is also responsible for MT-mediated nuclear targeting of adenovirus type 2 (Ad2). Here we show that treatment with low concentrations ...
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.132275599
更新日期:2002-08-06 00:00:00
abstract::Healthy ocean ecosystems are needed to sustain people and livelihoods and to achieve the United Nations Sustainable Development Goals. Using the ocean sustainably requires overcoming many formidable challenges: overfishing, climate change, ocean acidification, and pollution. Despite gloomy forecasts, there is reason f...
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.1604982113
更新日期:2016-12-20 00:00:00
abstract::Previous work has established stargazin and its related family of transmembrane AMPA receptor regulatory proteins (TARPs) as auxiliary subunits of AMPA receptors (AMPARs) that control synaptic strength both by targeting AMPARs to synapses through an intracellular PDZ-binding motif and by modulating their gating throug...
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.0905570106
更新日期:2009-07-07 00:00:00
abstract::In adult rodents, neurons are continually generated in the subventricular zone of the forebrain, from where they migrate tangentially toward the olfactory bulb, the only known target for these neuronal precursors. Within the main olfactory bulb, they ascend radially into the granule and periglomerular cell layers, whe...
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.97.4.1823
更新日期:2000-02-15 00:00:00
abstract::A readily accessible new class of near infrared (NIR) molecular probes has been synthesized and evaluated. Specific fluorophores in this unique xanthene based regioisomeric seminaphthofluorone dye series exhibit a combination of desirable characteristics including (i) low molecular weight (339 amu), (ii) aqueous solub...
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.0710341105
更新日期:2008-07-01 00:00:00
abstract::Human rhinovirus (HRV) and other members of the enterovirus genus bind small-molecule antiviral compounds in a cavity buried within the viral capsid protein VP1. These compounds block the release of the viral protein VP4 and RNA from inside the capsid during the uncoating process. In addition, the antiviral compounds ...
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.1119174109
更新日期:2012-04-03 00:00:00
abstract::Utilization of transcription factors might be a powerful approach to modification of metabolism for a generation of crops having superior characteristics because a single transcription factor frequently regulates coordinated expression of a set of key genes for respective pathways. Here, we apply the plant-specific Do...
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.0402267101
更新日期:2004-05-18 00:00:00
abstract::Developing autoreactive B cells edit their B cell antigen receptor (BCR) in the bone marrow and are clonally deleted when they fail to reexpress an innocent BCR. Here, inducible Cre-loxP-mediated gene inversion is used to change the specificity of the BCR on mature IgM+ IgD+ B cells in vivo to address the fate of lymp...
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.95.22.13171
更新日期:1998-10-27 00:00:00
abstract::AMPA-type glutamate receptor (AMPAR) trafficking is essential for modulating synaptic transmission strength. Prior studies that have characterized signaling pathways underlying AMPAR trafficking have identified the cAMP/PKA-mediated phosphorylation of GluA1, an AMPAR subunit, as a key step in the membrane insertion 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.1311783110
更新日期:2013-09-17 00:00:00
abstract::The MYC family of cellular oncogenes includes c-Myc, N-myc, and L-myc, which encode transcriptional regulators involved in the control of cell proliferation and death. Accordingly, these genes become aberrantly activated and expressed in specific types of cancers. For example, c-Myc translocations occur frequently 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.0812763106
更新日期:2009-02-17 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::Mechanoelectrical transduction in the inner ear is a biophysical process underlying the senses of hearing and balance. The key players involved in this process are mechanosensitive ion channels. They are located in the stereocilia of hair cells and opened by the tension in specialized molecular springs, the tip links,...
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.1713135114
更新日期:2017-12-19 00:00:00
abstract::A glucose-responsive "closed-loop" insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch ("smart insulin patch") containi...
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.1505405112
更新日期:2015-07-07 00:00:00
abstract::Overexpression of the receptor tyrosine kinase (RTK) erbB2 (also designated neu or HER2) was implicated in causing a variety of human cancers, including mammary and ovarian carcinomas. Ligand-induced receptor dimerization is critical for stimulation of the intrinsic protein tyrosine kinase (PTK) of RTKs. It was theref...
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.252640799
更新日期:2002-12-10 00:00:00
abstract::Despite the widespread use of silicon in modern technology, its peculiar thermal expansion is not well understood. Adapting harmonic phonons to the specific volume at temperature, the quasiharmonic approximation, has become accepted for simulating the thermal expansion, but has given ambiguous interpretations for micr...
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.1707745115
更新日期:2018-02-27 00:00:00
abstract::Four macrocyclic cystine-knot peptides of 29-31 residues, kalata, circulin A and B (CirA and CirB), and cyclopsychotride, have been isolated from coffee plants but have undetermined physiological functions. These macrocycles and 10 of their analogs prepared by chemical synthesis were tested against nine strains of mic...
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.96.16.8913
更新日期:1999-08-03 00:00:00
abstract::Despite structural knowledge of broadly neutralizing monoclonal antibodies (NMAbs) complexed to HIV-1 gp120 and gp41 envelope glycoproteins, virus inactivation mechanisms have been difficult to prove, in part because neutralization assays are complex and were previously not understood. Concordant with recent evidence ...
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.1109728109
更新日期:2012-05-15 00:00:00
abstract::Human cDNA clones encoding a structure-specific recognition protein, SSRP1, that binds specifically to DNA modified with cisplatin have been isolated and characterized. The SSRP1 gene maps to human chromosome 11q12. The cDNA clones, obtained by using partial-length cDNAs described previously, predict an 81-kDa protein...
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.89.6.2307
更新日期:1992-03-15 00:00:00
abstract::Gentamicin C complex from Micromonospora echinospora remains a globally important antibiotic, and there is revived interest in the semisynthesis of analogs that might show improved therapeutic properties. The complex consists of five components differing in their methylation pattern at one or more sites in the molecul...
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.1711603115
更新日期:2018-02-06 00:00:00
abstract::The quorum sensing signal autoinducer-2 (AI-2) regulates important bacterial behaviors, including biofilm formation and the production of virulence factors. Some bacteria, such as Escherichia coli, can quench the AI-2 signal produced by a variety of species present in the environment, and thus can influence AI-2-depen...
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.1408691111
更新日期:2014-09-30 00:00:00
abstract::The transcription factor interferon regulatory factor 5 (IRF5) is essential for the induction of inflammatory cytokines, but the mechanism by which IRF5 is activated is not well understood. Here we present evidence that the kinase IKKβ phosphorylates and activates IRF5 in response to stimulation in several inflammator...
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.1418516111
更新日期:2014-12-09 00:00:00
abstract::It is generally accepted that healthy cells degrade their own mitochondria. Here, we report that retinal ganglion cell axons of WT mice shed mitochondria at the optic nerve head (ONH), and that these mitochondria are internalized and degraded by adjacent astrocytes. EM demonstrates that mitochondria are shed through f...
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.1404651111
更新日期:2014-07-01 00:00:00