Abstract：
:Trimeric class I virus fusion proteins undergo a series of conformational rearrangements that leads to the association of C- and N-terminal heptad repeat domains in a "trimer-of-hairpins" structure, facilitating the apposition of viral and cellular membranes during fusion. This final fusion hairpin structure is sustained by protein-protein interactions, associations thought initially to be refractory to small-molecule inhibition because of the large surface area involved. By using a photoaffinity analog of a potent respiratory syncytial virus fusion inhibitor, we directly probed the interaction of the inhibitor with its fusion protein target. Studies have shown that these inhibitors bind within a hydrophobic cavity formed on the surface of the N-terminal heptad-repeat trimer. In the fusogenic state, this pocket is occupied by key amino acid residues from the C-terminal heptad repeat that stabilize the trimer-of-hairpins structure. The results indicate that a low-molecular-weight fusion inhibitor can interfere with the formation or consolidation of key structures within the hairpin moiety that are essential for membrane fusion. Because analogous cavities are present in many class I viruses, including HIV, these results demonstrate the feasibility of this approach as a strategy for drug discovery.
journal_name
Proc Natl Acad Sci U S Aauthors
Cianci C,Langley DR,Dischino DD,Sun Y,Yu KL,Stanley A,Roach J,Li Z,Dalterio R,Colonno R,Meanwell NA,Krystal Mdoi
10.1073/pnas.0406696101keywords:
subject
Has Abstractpub_date
2004-10-19 00:00:00pages
15046-51issue
42eissn
0027-8424issn
1091-6490pii
0406696101journal_volume
101pub_type
杂志文章abstract：:Adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] was solubilized from a rat brain homogenate with sodium deoxycholate. This solubilized preparation had no detectable enzymic activity with either Mg-ATP or Mn-ATP as substrate. The activity could be restored by addition of either nonionic detergent or...
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.78.1.120
更新日期：1981-01-01 00:00:00
abstract：:We explored the conformational landscape of the proteinogenic amino acid serine [CH(2)OH CH(NH(2)) COOH] in the gas phase. Solid serine was vaporized by laser ablation, expanded in a supersonic jet, and characterized by Fourier transform microwave spectroscopy. In the isolation conditions of the jet there have been di...
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.0705676104
更新日期：2007-12-18 00:00:00
abstract：:We explore the interactions of CYT-19, a DExD/H-box protein that functions in folding of group I RNAs, with a well characterized misfolded species of the Tetrahymena ribozyme. Consistent with its function, CYT-19 accelerates refolding of the misfolded RNA to its native state. Unexpectedly, CYT-19 performs another reac...
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.0603127103
更新日期：2006-11-07 00:00:00
abstract：:Newborns are at increased risk of jaundice, a condition in which excess bilirubin accumulates in blood. Left untreated, jaundice can lead to neurological impairment and death. Jaundice resulting from unconjugated hyperbilirubinemia is easily treated with exposure to blue light, and phototherapy systems have been devel...
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.1714020114
更新日期：2017-12-19 00:00:00
abstract：:The effects of three anti-inflammatory drugs, which interfere with arachidonic acid transformation by three different enzymes, have been compared by using a simple model of tissue damage and foreign body rejection. In groups of control rats, subcutaneously implanted polyester sponges were rejected after a mean of 12 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.81.9.2890
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abstract：:A low molecular weight toxin isolated from the venom of the digger wasp Philanthus triangulum, first noted by T. Piek, is a potent antagonist of transmission at quisqualate-sensitive glutamate synapses of locust leg muscle. This philanthotoxin 433 (PTX-433) has been purified, chemically characterized, and subsequently...
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.85.13.4910
更新日期：1988-07-01 00:00:00
abstract：:The lactose permease (LacY) of Escherichia coli, a paradigm for the major facilitator superfamily, catalyzes the coupled stoichiometric translocation of a galactopyranoside and an H(+) across the cytoplasmic membrane. To catalyze transport, LacY undergoes large conformational changes that allow alternating access of s...
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.1404446111
更新日期：2014-04-22 00:00:00
abstract：:The copy number of plasmid ColE1 has been known to increase when the Hae II-C segment downstream from the replication origin is deleted. The presence of the 306-base-pair (bp) Hpa II region in the segment is sufficient for reduction of the copy number. Plasmids harboring the region express a trans-acting function that...
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.80.11.3232
更新日期：1983-06-01 00:00:00
abstract：:The importance of dystrophin and its associated proteins in normal muscle function is now well established. Many of these proteins are expressed in nonmuscle tissues, particularly the brain. Here we describe the characterization of beta-dystrobrevin, a dystrophin-related protein that is abundantly expressed in brain a...
journal_title：Proceedings of the National Academy of Sciences of the United States of America
pub_type： 杂志文章
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更新日期：1998-01-06 00:00:00
abstract：:Efficient and productive virus infection often requires viral countermeasures that block innate immunity. The IFN-inducible 2',5'-oligoadenylate (2-5A) synthetases (OASs) and ribonuclease (RNase) L are components of a potent host antiviral pathway. We previously showed that murine coronavirus (MHV) accessory protein 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.1306917110
更新日期：2013-08-06 00:00:00
abstract：:Autocatalytic activation of an initiator caspase triggers the onset of apoptosis. In dying cells, caspase-9 activation is mediated by a multimeric adaptor complex known as the Apaf-1 apoptosome. The molecular mechanism by which caspase-9 is activated by the Apaf-1 apoptosome remains largely unknown. Here we demonstrat...
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.1418000111
更新日期：2014-11-18 00:00:00
abstract：:Developmental genetic studies of evolved differences in morphology have led to the hypothesis that cis-regulatory changes often underlie morphological evolution. However, because most of these studies focus on evolved loss of traits, the genetic architecture and possible association with cis-regulatory changes of gain...
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.1407567111
更新日期：2014-09-23 00:00:00
abstract：:Glucocorticoids (GCs) are potent anti-inflammatory agents that block cytokine production. We investigated whether GCs also block cytokine signaling via the Janus kinase (Jak)-signal transducer and activator of transcription (STAT) pathway. Dexamethasone inhibited IL-2-induced DNA binding, tyrosine phosphorylation, 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.160099797
更新日期：2000-08-15 00:00:00
abstract：:Differences in T cell receptor (TCR) signaling initiated by interactions among TCRs, coreceptors, and self-peptide-MHC complexes determine the outcome of CD4 versus CD8 lineage of T cell differentiation. The H-2Ld and Kbm3 alloreactive 2C TCR is positively selected by MHC class I Kb and a yet-to-be identified nonclass...
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.0510561103
更新日期：2006-02-07 00:00:00
abstract：:The mitochondrial contact site and cristae organizing system (MICOS) is a multisubunit protein complex that is essential for the proper architecture of the mitochondrial inner membrane. MICOS plays a key role in establishing and maintaining crista junctions, tubular or slit-like structures that connect the cristae mem...
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.2009364117
更新日期：2020-08-25 00:00:00
abstract：:Positional cloning has already produced the sequences of more than 70 human genes associated with specific diseases. In addition to their medical importance, these genes are of interest as a set of human genes isolated solely on the basis of the phenotypic effect of the respective mutations. We analyzed the protein se...
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.94.11.5831
更新日期：1997-05-27 00:00:00
abstract：:The unicellular green alga Chlamydomonas swims with two flagella that can synchronize their beat. Synchronized beating is required to swim both fast and straight. A long-standing hypothesis proposes that synchronization of flagella results from hydrodynamic coupling, but the details are not understood. Here, we presen...
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.1300895110
更新日期：2013-11-05 00:00:00
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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.1303738110
更新日期：2013-06-18 00:00:00
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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.1504280112
更新日期：2015-04-28 00:00:00
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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.1301826110
更新日期：2013-05-28 00:00:00
abstract：:We recognize, understand, and interact with objects through both vision and touch. Conceivably, these two sensory systems encode object shape in similar ways, which could facilitate cross-modal communication. To test this idea, we studied single neurons in macaque monkey intermediate visual (area V4) and somatosensory...
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.0904186106
更新日期：2009-09-22 00:00:00
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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.92.16.7600
更新日期：1995-08-01 00:00:00
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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.1702586114
更新日期：2017-08-22 00:00:00
abstract：:Allostery, the coupling between ligand binding and protein conformational change, is the heart of biological network and it has often been explained by two representative models, the induced-fit and the population-shift models. Here, we clarified for what systems one model fits better than the other by performing mole...
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.0802524105
更新日期：2008-08-12 00:00:00
abstract：:The neural crest (NC) emerges from combinatorial inductive events occurring within its progenitor domain, the neural border (NB). Several transcription factors act early at the NB, but the initiating molecular events remain elusive. Recent data from basal vertebrates suggest that ap2 might have been critical for NC em...
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.1010740107
更新日期：2011-01-04 00:00:00
abstract：:ATP-sensitive potassium channels (K(ATP)) are involved in a diverse array of physiologic functions including protection of tissue against ischemic insult, regulation of vascular tone, and modulation of insulin secretion. To improve our understanding of the role of K(ATP) in these processes, we used a gene-targeting st...
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.201390398
更新日期：2001-09-25 00:00:00
abstract：:The temporal and spatial patterns of floral determination in cultured internode segments of Nicotiana tabacum L. cv. Wisconsin 38 were investigated. Segments from internodes, when cultured on hormone-free medium, either produced some de novo floral shoots or produced only vegetative shoots. Segments that produced some...
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.84.9.2790
更新日期：1987-05-01 00:00:00
abstract：:A number of recent studies have shown that iron dissolution in Fe-containing dust aerosol can be linked to source material (mineral or anthropogenic), mineralogy, and iron speciation. All of these factors need to be incorporated into atmospheric chemistry models if these models are to accurately predict the impact 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.0910809107
更新日期：2010-04-13 00:00:00
abstract：:The nucleus accumbens (NAc) regulates motivated behavior by, in part, processing excitatory synaptic projections from several brain regions. Among these regions, the prefrontal cortex (PFC) and basolateral amygdala, convey executive control and affective states, respectively. Whereas glutamatergic synaptic transmissio...
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.1206287110
更新日期：2013-01-08 00:00:00
abstract：:The formation of social attachments is a critical component of human relationships. Infants begin to bond to their caregivers from the moment of birth, and these social bonds continue to provide regulatory emotional functions throughout adulthood. It is difficult to examine the interactions between social experience 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.0504767102
更新日期：2005-11-22 00:00:00
