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81.
Chi Shing Sum Irina G. Tikhonova Stefano Costanzi Marvin C. Gershengorn 《The Journal of biological chemistry》2009,284(6):3529-3536
Activation of a number of class A G protein-coupled receptors (GPCRs) is
thought to involve two molecular switches, a rotamer toggle switch within the
transmembrane domain and an ionic lock at the cytoplasmic surface of the
receptor; however, the mechanism by which agonist binding changes these
molecular interactions is not understood. Importantly, 80% of GPCRs including
free fatty acid receptor 1 (FFAR1) lack the complement of amino acid residues
implicated in either or both of these two switches; the mechanism of
activation of these GPCRs is therefore less clear. By homology modeling, we
identified two Glu residues (Glu-145 and Glu-172) in the second extracellular
loop of FFAR1 that form putative interactions individually with two
transmembrane Arg residues (Arg-183(5.39) and Arg-258(7.35)) to create two
ionic locks. Molecular dynamics simulations showed that binding of agonists to
FFAR1 leads to breakage of these Glu-Arg interactions. In mutagenesis
experiments, breakage of these two putative interactions by substituting Ala
for Glu-145 and Glu-172 caused constitutive receptor activation. Our results
therefore reveal a molecular switch for receptor activation present on the
extracellular surface of FFAR1 that is broken by agonist binding. Similar
ionic locks between the transmembrane domains and the extracellular loops may
constitute a mechanism common to other class A GPCRs also.G protein-coupled receptors
(GPCRs)3 are important
components of signal transduction machineries that regulate many physiological
processes. They are also important as targets for therapeutic agents; a large
percentage of drugs in the marketplace are GPCR ligands or modulators.
Knowledge of structure-function relationships of GPCRs has been gained through
many pharmacological, biochemical, and biophysical studies, and has been used
extensively to enhance the discovery of GPCR ligands that have been developed
into therapeutically useful agents
(1–3).
Knowledge of the molecular details of ligand-receptor interaction and of the
mechanism of receptor activation will also likely improve efforts to identify
agonists with better potency and efficacy. Tan et al.
(3) have recently reported
their design of agonists with higher potency and efficacy for the trace amine
receptor 1 based on the rotamer toggle switch model of receptor activation
that is thought to operate in a number of class A GPCRs. The rotamer toggle
switch typically involves the aromatic residues Trp and Phe within
transmembrane helix 6 (TMH6) of GPCRs. During agonist-mediated receptor
activation or in constitutively active receptors, the dihedral angle on the
side chain of these residues is predicted to be rotated compared with the
inactive state and thereby triggers a movement of TMH6 away from TMH3
(e.g. Ref. 4). It is
also thought that an ionic lock between an Arg residue in TMH3 and a Glu in
TMH6 near the cytoplasmic surface of some GPCRs holds the receptor in the
inactive conformation and that receptor activation is accompanied by breakage
of the ionic bond when agonist binds; the ionic lock may also be broken by
receptor mutation (e.g. Ref.
5). Although these models of
receptor activation have been proposed for a number of class A GPCRs, it is
not certain how generally this hypothesis can be applied across all members of
this GPCR class. From the alignment of 372 sequences of human GPCRs, we noted
that about 80% of GPCRs do not have the putative residues that play a role in
either the rotamer toggle switch, the ionic lock, or both. For these
receptors, the interaction responsible for regulating interconversion between
inactive and active receptor conformations therefore remains unknown.The free fatty acid receptor 1 (FFAR1) is a Gq-coupled, class A
GPCR-activated endogenously by free fatty acids, with a preference for
medium-to-long chain fatty acids (C8–12) (reviewed in Ref.
6). The receptor has been
suggested to be a potential target for treatment of type 2 diabetes, as
offered by the action of agonists to potentiate glucose-stimulated insulin
release (reviewed in Refs. 7,
8). Several groups, including
ours, have reported the discovery of novel small molecule ligands for FFAR1
(9–13).
Most of these compounds were identified by high-throughput screening followed
by chemical optimization
(10–12).
Our group has delineated the ligand-binding pocket of FFAR1
(14,
15) and used the information
as a rational approach to ligand discovery by means of virtual screening
(13). The mechanism of FFAR1
activation; however, remains unknown especially because this receptor does not
contain either the rotamer toggle switch or the ionic lock between TMHs 3 and
6.We have previously identified nine residues in the ligand-binding pocket of
FFAR1 that are important for ligand recognition and/or receptor activation
(14). In particular, two Arg
residues
(Arg-183(5.39)4 and
Arg-258(7.35)) and an Asn residue (Asn-244(6.55)) in the TMHs coordinate the
carboxylate head group of the naturally occurring agonist linoleate and the
synthetic agonist GW9508. In the present study, by a collaborative effort
using computational modeling and receptor mutagenesis, we report the
identification of Glu-172 in the second extracellular loop (ECL2) of FFAR1
that may function together with Arg-183(5.39) and Arg-258(7.35) as locks to
control activation of the receptor. Our results suggest that these ionic locks
at the extracellular surface hold the receptor in an inactive state. Agonists,
through interaction with the arginine residues, may break the
arginine-glutamate interactions thereby allowing the receptor to adopt an
active conformation. Therefore, our results have provided insights into the
mechanism of activation of class A GPCRs that function in a manner not
explicable by the more well-studied models. 相似文献
82.
Kuver R Wong T Klinkspoor JH Lee SP 《American journal of physiology. Gastrointestinal and liver physiology》2006,291(6):G1148-G1154
Mucus of cystic fibrosis patients exhibits altered biochemical composition and biophysical behavior, but the causal relationships between altered cystic fibrosis transmembrane conductance regulator (CFTR) function and the abnormal mucus seen in various organ systems remain unclear. We used cultured gallbladder epithelial cells (GBEC) from wild-type and Cftr((-/-)) mice to investigate mucin gene and protein expression, kinetics of postexocytotic mucous granule content expansion, and biochemical and ionic compositions of secreted mucins. Muc1, Muc3, Muc4, Muc5ac, and Muc5b mRNA levels were significantly lower in Cftr((-/-)) GBEC compared with wild-type cells, whereas Muc2 mRNA levels were higher in Cftr((-/-)) cells. Quantitative immunoblotting demonstrated a trend toward lower MUC1, MUC2, MUC3, MUC5AC, and MUC5B mucin levels in Cftr((-/-)) cells compared with cells from wild-type mice. In contrast, the levels of secreted MUC1, MUC3, MUC5B, and MUC6 mucins were significantly higher from Cftr((-/-)) cells; a trend toward higher levels of secreted MUC2 and MUC5AC was also noted from Cftr((-/-)) cells. Cftr((-/-)) cells demonstrated slower postexocytotic mucous granule content expansion. Calcium concentration was significantly elevated in the mucous gel secreted by Cftr((-/-)) cells compared with wild-type cells. Secreted mucins from Cftr((-/-)) cells contained higher sulfate concentrations. Thus absence of CFTR is associated with pleiotropic effects on mucins in murine GBEC. 相似文献
83.
Oxysterols are naturally occurring intermediates in the conversion of cholesterol to bile acids, the major route for elimination of cholesterol. Additionally, they are important signaling agents, particularly in control of cholesterol synthesis; however, some species also are cytotoxic and carcinogenic. Oxysterols in plasma, contained in oxidized low-density lipoprotein, are strongly correlated with atherosclerosis. Oxysterols are found in infected human bile and the oxysterol content in gallstones correlates with bacterial DNA in the stones. Here we demonstrate that human leukocytes, activated by the presence of bacterial lipopolysaccharide, are able to oxidize cholesterol to a variety of oxysterols, including species known to be carcinogenic. 相似文献
84.
Variable number tandem repeat (VNTR) typing of Mycobacterium tuberculosis, as presently used, has often failed to differentiate clonal strains especially in areas where the Beijing family genotype is predominant. We have evaluated mycobacterial interspersed repetitive units (MIRUs), Queen's University of Belfast (QUB) loci and exact tandem repeat (ETR) loci individually for their abilities to differentiate the Beijing and non-Beijing genotype families of M. tuberculosis. The best locus was QUB 3232 followed by QUB 11b. Available MIRU, QUB and ETR loci were then consecutively arranged in declining order of discriminatory power, and combined to form an optimal set of 12-loci VNTR typing (MIRU 10, 26, 39, 40; QUB 11a, 11b, 15, 18, 26, 3232, 3336; ETR A) that possessed comparable discriminatory ability to IS6110 restriction fragment length polymorphism. This optimized 12-loci VNTR typing set can become an important tool for tracking M. tuberculosis of the Beijing family. 相似文献
85.
A number of 9-acylamino and 9-sulfonylamino derivatives of minocycline have been synthesized for structure-activity relationship studies. These compounds showed activity against both tetracycline-susceptible and tetracycline-resistant strains. Many of the 9-sulfonylamino derivatives exhibited improved antibacterial activity against a number of tetracycline- and minocycline-resistant Gram-positive pathogens. 相似文献
86.
87.
S Kuhla Dr Monika Klein Ulla Renne W Jentsch PE Rudolph WB Souffrant 《Archives of animal nutrition》2013,67(1):37-46
The objective of this study was to explore whether the C and N content can be used to estimate the fat content of animal carcasses. Considering the mean C and N contents of body fat and body protein, the fat content (EE) [%] can be predicted from C and N values [%] according to the generally valid equation EE=1.3038·C – 4.237·N. The application of this equation to estimate the total fat content of all animal carcasses results in significant differences in fat content between predicted and measured values. Therefore, we derived specific equations for rats, pigs, cattle, sheep, broilers and mice to predict the fat content by dual linear regression analysis (y=EE [% DM], x1=C [% DM], x2=N [% DM]) based on measured fat, C, and N contents of animal body samples. The specific equations for different animals showed residual standard deviations of 1.55, 1.63, 1.12, 1.35, 1.85 and 0.92% fat for rats, pigs, cattle, sheep, broilers and mice, respectively. 相似文献
88.
Kamil A. Braima Jia-Siang Sum Amir-Ridhwan M. Ghazali Mustakiza Muslimin John Jeffery Wenn-Chyau Lee Mohammed R. Shaker Alaa-Eldeen M. Elamin Ibrahim Jamaiah Yee-Ling Lau Mahmud Rohela Adeeba Kamarulzaman Frankie Sitam Rosnida Mohd-Noh Noraishah M. Abdul-Aziz 《PloS one》2013,8(10)
Background
The suburban transmission of malaria in Selangor, Malaysia’s most developed and populous state still remains a concern for public health in this region. Despite much successful control efforts directed at its reduction, sporadic cases, mostly brought in by foreigners have continued to occur. In addition, cases of simian malaria caused by Plasmodium knowlesi, some with fatal outcome have caused grave concern to health workers. The aim of this study was to investigate the possibility of local malaria transmission in suburban regions of Selangor, which are adjacent to secondary rainforests.Findings
A malaria survey spanning 7 years (2006 - 2012) was conducted in Selangor. A total of 1623 laboratory confirmed malaria cases were reported from Selangor’s nine districts. While 72.6% of these cases (1178/1623) were attributed to imported malaria (cases originating from other countries), 25.5% (414/1623) were local cases and 1.9% (31/1623) were considered as relapse and unclassified cases combined. In this study, the most prevalent infection was P. vivax (1239 cases, prevalence 76.3%) followed by P. falciparum (211, 13.0%), P. knowlesi (75, 4.6%), P. malariae (71, 4.4%) and P. ovale (1, 0.06%). Mixed infections comprising of P. vivax and P. falciparum were confirmed (26, 1.6%). Entomological surveys targeting the residences of malaria patients’ showed that the most commonly trapped Anopheles species was An. maculatus. No oocysts or sporozoites were found in the An. maculatus collected. Nevertheless, the possibility of An. maculatus being the malaria vector in the investigated locations was high due to its persistent occurrence in these areas.Conclusions
Malaria cases reported in this study were mostly imported cases. However the co-existence of local cases and potential Plasmodium spp. vectors should be cause for concern. The results of this survey reflect the need of maintaining closely monitored malaria control programs and continuous extensive malaria surveillance in Peninsula Malaysia. 相似文献89.
90.
FRANCISCA FUENTES‐RODRÍGUEZ MELCHOR JUAN IRENE GALLEGO MIRIAN LUSI ENCARNACIÓN FENOY DAVID LEÓN PATRICIO PEÑALVER JULIA TOJA J. JESÚS CASAS 《Freshwater Biology》2013,58(1):63-78
1. Agricultural intensification has caused dramatic biodiversity loss in many agricultural landscapes over the last century. Here, we investigated whether new types of farm ponds (made of artificial substrata) in intensive systems and natural‐substratum ponds in traditional farming systems differ in their value for aquatic biodiversity conservation. 2. We analysed the main patterns of environmental variation, compared α‐, β‐ and γ‐diversity of macroinvertebrates between ponds types and evaluated the role of submerged aquatic vegetation (SAV). Generalised additive models (GAM) were used to analyse the relationships of α‐ and β‐diversity with environmental predictors, and variation partitioning to separate the effect of environmental and spatial characteristics on the variation in macroinvertebrate assemblages. Moran’s eigenvector maps (MEMs) were used to define spatial variables. 3. A principal coordinate analysis (PCoA) detected a primary environmental gradient that separated nutrient‐rich ponds from those dominated by SAV; a secondary morphometric gradient distinguished natural‐substratum ponds, with large surface area and structural complexity, from artificial‐substratum ponds with steeper slopes. Natural‐substratum ponds had almost twice the α‐ and γ‐diversity of artificial‐substratum ponds, and diversity significantly increased when SAV was present, particularly in artificial‐substratum ponds. Total phosphorus (TP) strongly contributed to explain the patterns in diversity, while SAV was a significant predictor of assemblage composition and diversity. GAMs revealed optima of both α‐diversity at intermediate SAV covers and β‐diversity at intermediate–high TP concentrations. 4. These findings have important implications for conservation planning. Adaptation of artificial‐substratum ponds by adding natural substratum and smoothing the gradient of pond margins would improve their conservation value. Development of SAV with occasional harvests and certain cautionary measures to control nutrient levels may also improve both the agronomical and environmental function of ponds. 相似文献