516 research outputs found
The extracellular surface of the GLP-1 receptor is a molecular trigger for biased agonism
Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists
Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy.
Class B peptide hormone GPCRs are targets for the treatment of major chronic disease. Peptide ligands of these receptors display biased agonism and this may provide future therapeutic advantage. Recent active structures of the calcitonin (CT) and glucagon-like peptide-1 (GLP-1) receptors reveal distinct engagement of peptides with extracellular loops (ECLs) 2 and 3, and mutagenesis of the GLP-1R has implicated these loops in dynamics of receptor activation. In the current study, we have mutated ECLs 2 and 3 of the human CT receptor (CTR), to interrogate receptor expression, peptide affinity and efficacy. Integration of these data with insights from the CTR and GLP-1R active structures, revealed marked diversity in mechanisms of peptide engagement and receptor activation between the CTR and GLP-1R. While the CTR ECL2 played a key role in conformational propagation linked to Gs/cAMP signalling this was mechanistically distinct from that of GLP-1R ECL2. Moreover, ECL3 was a hotspot for distinct ligand- and pathway- specific effects, and this has implications for the future design of biased agonists of class B GPCRs
Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor
Class B GPCRs can activate multiple signalling effectors with the potential to exhibit biased agonism in response to ligand stimulation. Previously, we highlighted key TM domain polar amino acids that were crucial for the function of the GLP-1 receptor, a key therapeutic target for diabetes and obesity. Using a combination of mutagenesis, pharmacological characterisation, mathematical and computational molecular modelling, this study identifies additional highly conserved polar residues located towards the TM helical boundaries of Class B GPCRs that are important for GLP-1 receptor stability and/or controlling signalling specificity and biased agonism. This includes (i) three positively charged residues (R3.30227, K4.64288, R5.40310) located at the extracellular boundaries of TMs 3, 4 and 5 that are predicted in molecular models to stabilise extracellular loop 2, a crucial domain for ligand affinity and receptor activation; (ii) a predicted hydrogen bond network between residues located in TMs 2 (R2.46176), 6 (R6.37348) and 7 (N7.61406 and E7.63408) at the cytoplasmic face of the receptor that is important for stabilising the inactive receptor and directing signalling specificity, (iii) residues at the bottom of TM 5 (R5.56326) and TM6 (K6.35346 and K6.40351) that are crucial for receptor activation and downstream signalling; (iv) residues predicted to be involved in stabilisation of TM4 (N2.52182 and Y3.52250) that also influence cell signalling. Collectively, this work expands our understanding of peptide-mediated signalling by the GLP-1 receptor
Global Search for New Physics with 2.0/fb at CDF
Data collected in Run II of the Fermilab Tevatron are searched for
indications of new electroweak-scale physics. Rather than focusing on
particular new physics scenarios, CDF data are analyzed for discrepancies with
the standard model prediction. A model-independent approach (Vista) considers
gross features of the data, and is sensitive to new large cross-section
physics. Further sensitivity to new physics is provided by two additional
algorithms: a Bump Hunter searches invariant mass distributions for "bumps"
that could indicate resonant production of new particles; and the Sleuth
procedure scans for data excesses at large summed transverse momentum. This
combined global search for new physics in 2.0/fb of ppbar collisions at
sqrt(s)=1.96 TeV reveals no indication of physics beyond the standard model.Comment: 8 pages, 7 figures. Final version which appeared in Physical Review D
Rapid Communication
Observation of Orbitally Excited B_s Mesons
We report the first observation of two narrow resonances consistent with
states of orbitally excited (L=1) B_s mesons using 1 fb^{-1} of ppbar
collisions at sqrt{s} = 1.96 TeV collected with the CDF II detector at the
Fermilab Tevatron. We use two-body decays into K^- and B^+ mesons reconstructed
as B^+ \to J/\psi K^+, J/\psi \to \mu^+ \mu^- or B^+ \to \bar{D}^0 \pi^+,
\bar{D}^0 \to K^+ \pi^-. We deduce the masses of the two states to be m(B_{s1})
= 5829.4 +- 0.7 MeV/c^2 and m(B_{s2}^*) = 5839.7 +- 0.7 MeV/c^2.Comment: Version accepted and published by Phys. Rev. Let
An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics
For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types
Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV
Results are presented from a search for a W' boson using a dataset
corresponding to 5.0 inverse femtobarns of integrated luminosity collected
during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV.
The W' boson is modeled as a heavy W boson, but different scenarios for the
couplings to fermions are considered, involving both left-handed and
right-handed chiral projections of the fermions, as well as an arbitrary
mixture of the two. The search is performed in the decay channel W' to t b,
leading to a final state signature with a single lepton (e, mu), missing
transverse energy, and jets, at least one of which is tagged as a b-jet. A W'
boson that couples to fermions with the same coupling constant as the W, but to
the right-handed rather than left-handed chiral projections, is excluded for
masses below 1.85 TeV at the 95% confidence level. For the first time using LHC
data, constraints on the W' gauge coupling for a set of left- and right-handed
coupling combinations have been placed. These results represent a significant
improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe
Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV
A search for a Higgs boson decaying into two photons is described. The
analysis is performed using a dataset recorded by the CMS experiment at the LHC
from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an
integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross
section of the standard model Higgs boson decaying to two photons. The expected
exclusion limit at 95% confidence level is between 1.4 and 2.4 times the
standard model cross section in the mass range between 110 and 150 GeV. The
analysis of the data excludes, at 95% confidence level, the standard model
Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The
largest excess of events above the expected standard model background is
observed for a Higgs boson mass hypothesis of 124 GeV with a local significance
of 3.1 sigma. The global significance of observing an excess with a local
significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is
estimated to be 1.8 sigma. More data are required to ascertain the origin of
this excess.Comment: Submitted to Physics Letters
Measurement of the Lambda(b) cross section and the anti-Lambda(b) to Lambda(b) ratio with Lambda(b) to J/Psi Lambda decays in pp collisions at sqrt(s) = 7 TeV
The Lambda(b) differential production cross section and the cross section
ratio anti-Lambda(b)/Lambda(b) are measured as functions of transverse momentum
pt(Lambda(b)) and rapidity abs(y(Lambda(b))) in pp collisions at sqrt(s) = 7
TeV using data collected by the CMS experiment at the LHC. The measurements are
based on Lambda(b) decays reconstructed in the exclusive final state J/Psi
Lambda, with the subsequent decays J/Psi to an opposite-sign muon pair and
Lambda to proton pion, using a data sample corresponding to an integrated
luminosity of 1.9 inverse femtobarns. The product of the cross section times
the branching ratio for Lambda(b) to J/Psi Lambda versus pt(Lambda(b)) falls
faster than that of b mesons. The measured value of the cross section times the
branching ratio for pt(Lambda(b)) > 10 GeV and abs(y(Lambda(b))) < 2.0 is 1.06
+/- 0.06 +/- 0.12 nb, and the integrated cross section ratio for
anti-Lambda(b)/Lambda(b) is 1.02 +/- 0.07 +/- 0.09, where the uncertainties are
statistical and systematic, respectively.Comment: Submitted to Physics Letters
Search for new physics in events with opposite-sign leptons, jets, and missing transverse energy in pp collisions at sqrt(s) = 7 TeV
A search is presented for physics beyond the standard model (BSM) in final
states with a pair of opposite-sign isolated leptons accompanied by jets and
missing transverse energy. The search uses LHC data recorded at a
center-of-mass energy sqrt(s) = 7 TeV with the CMS detector, corresponding to
an integrated luminosity of approximately 5 inverse femtobarns. Two
complementary search strategies are employed. The first probes models with a
specific dilepton production mechanism that leads to a characteristic kinematic
edge in the dilepton mass distribution. The second strategy probes models of
dilepton production with heavy, colored objects that decay to final states
including invisible particles, leading to very large hadronic activity and
missing transverse energy. No evidence for an event yield in excess of the
standard model expectations is found. Upper limits on the BSM contributions to
the signal regions are deduced from the results, which are used to exclude a
region of the parameter space of the constrained minimal supersymmetric
extension of the standard model. Additional information related to detector
efficiencies and response is provided to allow testing specific models of BSM
physics not considered in this paper.Comment: Replaced with published version. Added journal reference and DO
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