Abstract：
:The cytokine interleukin 13 (IL-13) is a major effector molecule for T-helper type 2 inflammation and is pathogenic in allergic diseases such as asthma. The effects of IL-13 are mediated via a pathway that is initiated by binding to a heterodimeric receptor consisting of IL-13Rα1 and IL-4Rα. Antibodies raised against IL-13 can block its inflammatory effects by interfering with binding to either of the two receptor polypeptides. Lebrikizumab is a monoclonal anti-IL-13 antibody that has shown clinical benefit in a phase II study for the treatment of moderate-to-severe uncontrolled asthma. Here we report the molecular structure of IL-13 in complex with the Fab from lebrikizumab by X-ray crystallography at 1.9Å resolution. We show that lebrikizumab inhibits IL-13 signaling by binding to IL-13 with very high affinity and blocking IL-13 binding to IL-4Rα. In addition, we use site-directed mutations to identify the most important antibody contributors to binding. Our studies define key features of lebrikizumab binding and its mechanism of action that may contribute to its clinical effects.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Ultsch M,Bevers J,Nakamura G,Vandlen R,Kelley RF,Wu LC,Eigenbrot Cdoi
10.1016/j.jmb.2013.01.024subject
Has Abstractpub_date
2013-04-26 00:00:00pages
1330-9issue
8eissn
0022-2836issn
1089-8638pii
S0022-2836(13)00040-5journal_volume
425pub_type
杂志文章abstract：:The energetic profiles of a significant number of protein-DNA systems at 20 degrees C reveal that, despite comparable Gibbs free energies, association with the major groove is primarily an enthalpy-driven process, whereas binding to the minor groove is characterized by an unfavorable enthalpy that is compensated by fa...
journal_title：Journal of molecular biology
pub_type： 杂志文章,评审
doi：10.1016/j.jmb.2006.09.059
更新日期：2007-01-05 00:00:00
abstract：:We have developed a novel method for the expression and purification of p27, the major core protein of simian immunodeficiency virus. Circular dichroism measurements of purified p27 were used to determine the relative amounts of alpha-helix, beta-sheet and unordered secondary structural elements. These empirically det...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/s0022-2836(05)80308-0
更新日期：1990-11-20 00:00:00
abstract：:Erythropoietin (Epo) is the humoral regulator of red blood-cell production. Low oxygen tension increases the Epo levels by enhancing transcription, through the hypoxia-inducible factor (HIF)-1, a transcriptional modulator in oxygen-regulated gene expression. In the present work, a cooperative interaction between hypox...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2003.12.023
更新日期：2004-02-06 00:00:00
abstract：:Huntington's disease (HD) is an inherited progressive neurodegenerative disorder caused by a pathological CAG trinucleotide repeat expansion in the large multi-exon gene, huntingtin (HTT). Although multiple pathogenic mechanisms have been proposed for HD, there is increasing interest in the RNA processing of the HTT g...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2013.12.028
更新日期：2014-04-03 00:00:00
abstract：:The autonomously replicating sequences (ARSs) of pSR1, a cryptic circular DNA plasmid detected in a strain of Zygosaccharomyces rouxii, were delimited by subcloning and deletion analysis and by the isolation of nucleotide substitution mutations. A 30 base-pair (bp) sequence from inverted repeat 1 (IR1) and presumably ...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/0022-2836(89)90242-8
更新日期：1989-06-20 00:00:00
abstract：:Complex and diverse signal transduction circuits are responsible for the efficient functioning of cellular network. Protein kinases and O-protein phosphatases are primarily responsible for propagating such stimuli within a eukaryotic cell. However, there is limited understanding of O-protein phosphatases in the prokar...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2005.07.004
更新日期：2005-09-23 00:00:00
abstract：:The entire DNA of Rhizobium meliloti MVII /1 cells was isolated preparatively by gentle lysis and sucrose gradient centrifugation. Fractions of the sucrose gradient were investigated by electron microscopy. We found intact megaplasmids in supercoiled and relaxed form and total chromosomes. The length of the megaplasmi...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/0022-2836(84)90475-3
更新日期：1984-05-15 00:00:00
abstract：:Peptide deformylases (PDFs) are essential enzymes of the N-terminal protein processing pathway of eubacteria. The recent discovery of two types of PDFs in higher plants, PDF1A and PDF1B, and the detection of PDF1A in humans, have raised questions concerning the importance of deformylation in eukaryotes. Here, we have ...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.2001.5175
更新日期：2001-12-07 00:00:00
abstract：:NADH:ubiquinone oxidoreductase (complex I) is the first and largest complex in the electron transport chain of mitochondria. The bovine complex purified from cardiac muscle consists of at least 42 different subunits with a combined molecular mass of about 890 kDa. The three-dimensional structure of the complex was det...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1998.1668
更新日期：1998-04-17 00:00:00
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journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2015.06.023
更新日期：2015-08-28 00:00:00
abstract：:K- and H-Ras are the most commonly mutated genes in human tumors and are critical for conferring and maintaining the oncogenic phenotype in tumors with poor prognoses. Here, we design genetically encoded antibody-like ligands (intrabodies) that recognize active, GTP-bound K- and H-Ras. These ligands, which use the 10t...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2016.11.008
更新日期：2017-02-17 00:00:00
abstract：:FLP is a conservative site-specific recombinase that is encoded by the 2 microns plasmid of the yeast, Saccharomyces cerevisiae. FLP is member of the integrase family of recombinases that mediate the recombination reaction through a Holliday intermediate. The FLP recognition target (FRT) sites lie within two 599 bp in...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1994.1647
更新日期：1994-10-21 00:00:00
abstract：:Despite the condensed nature of terminal sequences, the telomeres are transcribed into a group of noncoding RNAs, including the TElomeric Repeat-containing RNA (TERRA). Since the discovery of TERRA, its evolutionary conserved function has been confirmed, and its involvement in telomere length regulation, heterochromat...
journal_title：Journal of molecular biology
pub_type： 杂志文章,评审
doi：10.1016/j.jmb.2020.01.034
更新日期：2020-07-10 00:00:00
abstract：:The ligation of a decadeoxynucleotide containing the EcoRI recognition site forms a series of multimers which appear to be curved based on observed anomalous gel migration in polyacrylamide gels. The degree of DNA curvature present in the recognition sequence, based upon the observed migration anomaly, can be altered ...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/0022-2836(88)90561-x
更新日期：1988-08-20 00:00:00
abstract：:The viral RNA-dependent RNA polymerases show a conserved structure where the fingers domain interacts with the top of the thumb domain to create a tunnel through which nucleotide triphosphates reach the active site. We have solved the crystal structures of poliovirus polymerase (3D(pol)) in complex with all four NTPs,...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2006.11.070
更新日期：2007-03-09 00:00:00
abstract：:Protein unfolding occurs at both low and high temperatures, although in most cases, only the high-temperature transition can be experimentally studied. A pressing question is how much the low- and high-temperature denatured states, although thermodynamically equivalent, are structurally and kinetically similar. We hav...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2012.02.002
更新日期：2012-04-13 00:00:00
abstract：:A 1.9 A resolution X-ray structure of the apo-form of Corynebacterium 2,5-diketo-d-gluconic acid reductase A (2,5-DKGR A), a member of the aldo-keto reductase superfamily, has been determined by molecular replacement using the NADPH-bound form of the same enzyme as the search model. 2,5-DKGR A catalyzes the NADPH-depe...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.2001.4739
更新日期：2001-06-22 00:00:00
abstract：:Pre-mRNA editing results in production of transcripts having nucleotide sequences differing from that of the DNA template. We describe the first example of RNA editing in the fruitfly Drosophila melanogaster. This editing occurs in an alternatively spliced adult head transcript arising from the single-copy nuclear 4f-...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1996.0365
更新日期：1996-06-28 00:00:00
abstract：:Cardiovascular homeostasis and blood pressure regulation are reliant, in part, on interactions between natriuretic peptide (NP) hormones and natriuretic peptide receptors (NPR). The C-type NPR (NPR-C) is responsible for clearance of NP hormones from the circulation, and displays a cross-reactivity for all NP hormones ...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2006.06.060
更新日期：2006-08-25 00:00:00
abstract：:The electrostatic interactions in the channels of OmpF and PhoE porins from Escherichia coli were analysed on the basis of a macroscopic multi-dielectric model of the protein-membrane complex derived from the respective porin X-ray structures. The membrane was represented as layers of distinct dielectric constants cor...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1994.1451
更新日期：1994-07-22 00:00:00
abstract：:The crystal and molecular structure of a triacylglyceride lipase (EC 3.1.1.3) from the fungus Rhizomucor miehei was analyzed using X-ray single crystal diffraction data to 1.9 A resolution. The structure was refined to an R-factor of 0.169 for all available data. The details of the molecular architecture and the cryst...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/0022-2836(92)90225-9
更新日期：1992-10-05 00:00:00
abstract：:The nuclear receptor pregnane X receptor (PXR) acts as a sensor for a broad variety of natural and synthetic lipophilic compounds, such as bile acids and rifampicin, and regulates the expression of proteins that are involved in the metabolism and transport of these compounds. PXR binds as a heterodimer with the retino...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2004.12.003
更新日期：2005-02-18 00:00:00
abstract：:Protein self-assembly is a common and essential biological phenomenon, and bacterial microcompartments present a promising model system to study this process. Bacterial microcompartments are large, protein-based organelles which natively carry out processes important for carbon fixation in cyanobacteria and the surviv...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2020.11.020
更新日期：2021-01-22 00:00:00
abstract：:The steps of UUC recognition by tRNAPhe were analysed by temperature-jump measurements. At ion concentrations close to physiological conditions we found three relaxation processes, which we assigned to (1) formation of codon-anticodon complexes, (2) a conformational change of the anticodon loop coupled with Mg2+ bindi...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/0022-2836(84)90085-8
更新日期：1984-04-25 00:00:00
abstract：:In the early stages of infection, gaining control of the cellular protein synthesis machinery including its ribosomes is the ultimate combat objective for a virus. To successfully replicate, viruses unequivocally need to usurp and redeploy this machinery for translation of their own mRNA. In response, the host trigger...
journal_title：Journal of molecular biology
pub_type： 杂志文章,评审
doi：10.1016/j.jmb.2018.04.040
更新日期：2018-07-06 00:00:00
abstract：:Mimivirus is the largest known virus. Using cryo-electron microscopy, the virus was shown to be icosahedral, covered by long fibers, and appears to have at least two lipid membranes within its protein capsid. A unique vertex, presumably for attachment and infection of the host, can be seen for particles that have a su...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2005.08.060
更新日期：2005-10-28 00:00:00
abstract：:Ferrochelatase (protoheme ferrolyase, EC 4.99.1.1) is the terminal enzyme in heme biosynthesis and catalyzes the insertion of ferrous iron into protoporphyrin IX to form protoheme IX (heme). Due to the many critical roles of heme, synthesis of heme is required by the vast majority of organisms. Despite significant inv...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2007.08.040
更新日期：2007-11-02 00:00:00
abstract：:We have analysed nucleotide sequences at the junction between simian virus 40 (SV40) and cellular DNA in the Fisher rat transformed line tsA30-N2. This line contains a single insertion of one complete SV40 genome with a terminal duplication of 267 nucleotides, the recombination sites being located at nucleotides 439 a...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/0022-2836(84)90057-3
更新日期：1984-07-25 00:00:00
abstract：:Catalase-1, one of four catalase activities of Neurospora crassa, is associated with non-growing cells and accumulates in asexual spores. It is a large, tetrameric, highly efficient, and durable enzyme that is active even at molar concentrations of hydrogen peroxide. Catalase-1 is oxidized at the heme by singlet oxyge...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2004.07.027
更新日期：2004-09-17 00:00:00
abstract：:A transcriptionally active sub-set of the dispersed mouse VL30 family of proviral genetic elements was shown to be highly transmissible as a murine leukaemia virus pseudotype. Newly acquired VL30 proviruses (present at 1 to 2 copies per cell) were shown to be transcriptionally active. These data substantiate the hypot...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/0022-2836(86)90485-7
更新日期：1986-03-05 00:00:00
