Abstract:
:A vaccine capable of stimulating protective antiviral antibody responses is needed to curtail the global AIDS epidemic caused by HIV-1. Although rarely elicited during the course of natural infection or upon conventional vaccination, the membrane-proximal ectodomain region (MPER) of the HIV-1 glycoprotein of M(r) 41,000 (gp41) envelope protein subunit is the target of 3 such human broadly neutralizing antibodies (BNAbs): 4E10, 2F5, and Z13e1. How these BNAbs bind to their lipid-embedded epitopes and mediate antiviral activity is unclear, but such information might offer important insight into a worldwide health imperative. Here, EPR and NMR techniques were used to define the manner in which these BNAbs differentially recognize viral membrane-encrypted residues configured within the L-shaped helix-hinge-helix MPER segment. Two distinct modes of antibody-mediated interference of viral infection were identified. 2F5, like 4E10, induces large conformational changes in the MPER relative to the membrane. However, although 4E10 straddles the hinge and extracts residues W672 and F673, 2F5 lifts up residues N-terminal to the hinge region, exposing L669 and W670. In contrast, Z13e1 effects little change in membrane orientation or conformation, but rather immobilizes the MPER hinge through extensive rigidifying surface contacts. Thus, BNAbs disrupt HIV-1 MPER fusogenic functions critical for virus entry into human CD4 T cells and macrophages either by preventing hinge motion or by perturbing MPER orientation. HIV-1 MPER features important for targeted vaccine design have been revealed, the implications of which extend to BNAb targets on other viral fusion proteins.
journal_name
Proc Natl Acad Sci U S Aauthors
Song L,Sun ZY,Coleman KE,Zwick MB,Gach JS,Wang JH,Reinherz EL,Wagner G,Kim Mdoi
10.1073/pnas.0901474106subject
Has Abstractpub_date
2009-06-02 00:00:00pages
9057-62issue
22eissn
0027-8424issn
1091-6490pii
0901474106journal_volume
106pub_type
杂志文章abstract::A discussion of the expected mechanism of radical reduction of carbonyl compounds by dihydroflavin as it relates to the structure of the carbonyl compound is provided. Factors which must be taken into account are the free energies of formation of the radical anions (CR2O), THE ACIDITY OF THE CONJUGATE ACID OF THE CARB...
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.72.5.1763
更新日期:1975-05-01 00:00:00
abstract::As root symbionts of cycad trees, cyanobacteria of the genus Nostoc produce beta-methylamino-l-alanine (BMAA), a neurotoxic nonprotein amino acid. The biomagnification of BMAA through the Guam ecosystem fits a classic triangle of increasing concentrations of toxic compounds up the food chain. However, because BMAA is ...
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.0404926101
更新日期:2004-08-17 00:00:00
abstract::Absorbance changes in untreated intact leaf discs, produced upon excitation with high-intensity red light, were shown to be due to the photooxidation of cytochrome b-559. At low intensities (<100 W/m2), photooxidation was almost undetectable. Photooxidation occurred with a half-time of 4.3 sec and an extent of 0.64 mo...
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.87.23.9295
更新日期:1990-12-01 00:00:00
abstract::Midbrain dopamine neurons play central roles in reward processing. It is widely assumed that all dopamine neurons encode the same information. Some evidence, however, suggests functional differences between subgroups of dopamine neurons, particularly with respect to processing nonrewarding, aversive stimuli. To direct...
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.0811507106
更新日期:2009-03-24 00:00:00
abstract::To better understand how the relatively flat antigen-combining sites of antibodies interact with the concave shaped substrate-binding clefts of proteases, we determined the structures of two antibodies in complex with the trypsin-like hepatocyte growth-factor activator (HGFA). The two inhibitory antibodies, Ab58 and 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.0708251104
更新日期:2007-12-11 00:00:00
abstract::In budding yeast, two transcription factors, Swi4 and Swi6, control the expression of important cell cycle regulatory proteins (the G1 cyclins, Cln1 and Cln2, and the cyclin-like Hcs26) as well as the HO gene, whose product initiates mating-type switching. Both Swi4 and Swi6 are components of a protein complex that fo...
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.89.24.11852
更新日期:1992-12-15 00:00:00
abstract::Vanilloid receptor subunit 1 (VR1) appears to play a critical role in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues. Thus, VR1 antagonists are useful compounds to unravel the contribution of this receptor to pain perception, as well as to induce analgesia. We h...
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.022285899
更新日期:2002-02-19 00:00:00
abstract::The oxygen isotope record of the last million years, as provided by a deep sea core sediment, is analyzed by a method recently developed in the theory of dynamical systems. The analysis suggests that climatic variability is the manifestation of a chaotic dynamics described by an attractor of fractal dimensionality. 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.83.3.536
更新日期:1986-02-01 00:00:00
abstract::Id2 is a natural inhibitor of the basic helix-loop-helix transcription factors and the retinoblastoma tumor suppressor protein. Active Id2 prevents differentiation and promotes cell-cycle progression and tumorigenesis in the nervous system. A key event that regulates Id2 activity during differentiation is translocatio...
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.0600168103
更新日期:2006-03-28 00:00:00
abstract::The origins and consequences of a regulatory T cell (Treg) disorder in systemic lupus erythematosus (SLE) are poorly understood. In the (NZBxNZW) F(1) mouse model of lupus, we found that CD4(+)Foxp3(+) Treg failed to maintain a competitive pool size in the peripheral lymphoid organs resulting in a progressive homeosta...
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.0903158107
更新日期:2010-01-05 00:00:00
abstract::To use recombinant DNA technology to functionally analyze mutations introduced into cloned eukaryotic genes, a rapid procedure is necessary to assay the steps along the gene expression pathway. Since cloned rat insulin genes are not transcribed efficiently after transfection into various cell lines, I have asked wheth...
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.79.19.5798
更新日期:1982-10-01 00:00:00
abstract::Recent evidence indicates there is a role for small membrane vesicles, including exosomes, as vehicles for intercellular communication. Exosomes secreted by most cell types can mediate transfer of proteins, mRNAs, and microRNAs, but their role in the transmission of infectious agents is less established. Recent studie...
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.1221899110
更新日期:2013-08-06 00:00:00
abstract::The human carcinogen vinyl chloride is metabolized in the liver to reactive intermediates which form N2,3-ethenoguanine in DNA. N2,3-Ethenoguanine is known to cause G----A transitions during DNA replication in Escherichia coli, and its formation may be a carcinogenic event in higher organisms. To investigate the repai...
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.89.19.9331
更新日期:1992-10-01 00:00:00
abstract::We have recently shown that the Alzheimer disease 40-residue amyloid beta-protein [A beta P-(1-40)] can form cation-selective channels when incorporated into planar lipid bilayers by fusion of liposomes containing the peptide. Since A beta P-(1-40) comprises portions of the putative extracellular and membrane-spanning...
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.90.22.10573
更新日期:1993-11-15 00:00:00
abstract::We have identified a subset of CD56(+)CD3(-) human natural killer (NK) cells that express CD4 and the HIV coreceptors CCR5 and CXCR4. These cells can be productively infected in vitro by both CCR5- and CXCR4-using molecular clones of HIV-1 in a CD4-dependent manner. Analysis of HIV-infected persons showed that viral 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.102672999
更新日期:2002-05-14 00:00:00
abstract::In the realm of protein-protein interactions, the assembly process of homooligomers plays a fundamental role because the majority of proteins fall into this category. A comprehensive understanding of this multistep process requires the characterization of the driving molecular interactions and the transient intermedia...
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.1320077110
更新日期:2013-12-03 00:00:00
abstract::Symmetric and asymmetric dimethylation of arginine are isomeric protein posttranslational modifications with distinct biological effects, evidenced by the methylation of arginine 3 of histone H4 (H4R3): symmetric dimethylation of H4R3 leads to repression of gene expression, while asymmetric dimethylation of H4R3 is as...
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.1106946108
更新日期:2011-12-20 00:00:00
abstract::The expansion of machine learning to high-stakes application domains such as medicine, finance, and criminal justice, where making informed decisions requires clear understanding of the model, has increased the interest in interpretable machine learning. The widely used Classification and Regression Trees (CART) have ...
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.1816748116
更新日期:2019-10-01 00:00:00
abstract::Yeast centromeric DNA (CEN DNA) binding factor 3 (CBF3) is a multisubunit protein complex that binds to the essential CDEIII element in CEN DNA. The four CBF3 proteins are required for accurate chromosome segregation and are considered to be core components of the yeast kinetochore. We have examined the structure of 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.96.7.3757
更新日期:1999-03-30 00:00:00
abstract::The main consequence of the Chernobyl accident has been an increase in papillary thyroid carcinomas (PTCs) in those exposed to radioactive fallout as young children. Our aim was to identify genomic alterations that are associated with exposure to radiation. We used array comparative genomic hybridization to analyze 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.1017137108
更新日期:2011-06-07 00:00:00
abstract::We present here direct evidence for the preservation of a transcriptional initiation sequence in a eukaryotic rRNA precursor: the 5'-end group for precursor to 17S rRNA (p17S RNA) from Dictyostelium discoideum is identified as the triphosphate residue pppA-. We also show that mature 5S RNA form Dictyostelium bears a 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.75.2.740
更新日期:1978-02-01 00:00:00
abstract::Ghrelin is a newly discovered peptide and an endogenous ligand for growth hormone (GH) secretagogue (GHS) receptor. It has been shown to possess various central and peripheral effects, including GH secretion, food intake, and gastric and cardiac effects. Ghrelin and the GHS receptor are expressed also in pancreatic is...
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.0502470102
更新日期:2006-01-24 00:00:00
abstract::The POT1-TPP1 heterodimer, the major telomere-specific single-stranded DNA-binding protein in mammalian cells, protects chromosome ends and contributes to the regulation of telomerase. The recent discovery of telomeric RNA raises the question of how POT1 faithfully binds telomeric ssDNA and avoids illicit RNA binding ...
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.0911099107
更新日期:2010-01-12 00:00:00
abstract::We have shown that rat glioma tumors contain a protein that crossreacts with antibody against mouse 2.5S nerve growth factor prepared in rabbit in microcomplement fixation assays and has analogous isoelectric points to all the hybrids of 2.5S nerve growth factor (a dimer). Partially purified protein preparations from ...
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.71.6.2347
更新日期:1974-06-01 00:00:00
abstract::Fatty acid transport protein 4 (FATP4), a transmembrane protein in the endoplasmic reticulum (ER), is a recently identified negative regulator of the ER-associated retinal pigment epithelium (RPE)65 isomerase necessary for recycling 11-cis-retinal, the light-sensitive chromophore of both rod and cone opsin visual pigm...
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.2012623117
更新日期:2020-12-15 00:00:00
abstract::An emergent viral pathogen termed severe fever with thrombocytopenia syndrome virus (SFTSV) is responsible for thousands of clinical cases and associated fatalities in China, Japan, and South Korea. Akin to other phleboviruses, SFTSV relies on a viral glycoprotein, Gc, to catalyze the merger of endosomal host and vira...
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.1603827113
更新日期:2016-06-28 00:00:00
abstract::Although prairie voles (Microtus ochrogaster) are socially monogamous, males vary in both sexual and spatial fidelity. Most males form pairbonds, cohabit with one female, and defend territories. Wandering males, in contrast, have expansive home ranges that overlap many males and females. In the laboratory, pairing is ...
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.0709116105
更新日期:2008-01-29 00:00:00
abstract::To examine the hypothesis that bone marrow consists of discrete stem cell regulatory volumes or domains, we studied spleen colony-forming unit (CFU-S) population growth kinetics in unirradiated WBB6F1-W/Wv mice receiving various doses of +/+ bone marrow cells. Assay of femoral marrow CFU-S content in the eight recipie...
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.79.3.840
更新日期:1982-02-01 00:00:00
abstract::Identified over a dozen years ago in the brain and pancreatic islet, βIV-spectrin is critical for the local organization of protein complexes throughout the nervous system. βIV-Spectrin targets ion channels and adapter proteins to axon initial segments and nodes of Ranvier in neurons, and βIV-spectrin dysfunction unde...
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.1314195110
更新日期:2013-10-22 00:00:00
abstract::The hypothetical scanning (HS) method is a general approach for calculating the absolute entropy and free energy by analyzing Boltzmann samples obtained by Monte Carlo (MC) or molecular dynamics techniques. With HS applied to a fluid, each configuration i of the sample is reconstructed by adding its atoms gradually 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.0308197101
更新日期:2004-06-22 00:00:00