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891.
Hyun-Kyung Choi Sun Choi Yoonji Lee Dong Wook Kang HyungChul Ryu Han-Joo Maeng Suk-Jae Chung Vladimir A. Pavlyukovets Larry V. Pearce Attila Toth Richard Tran Yun Wang Matthew A. Morgan Peter M. Blumberg Jeewoo Lee 《Bioorganic & medicinal chemistry》2009,17(2):690-698
A series of non-vanillyl resiniferatoxin analogues, having 4-methylsulfonylaminophenyl and fluorophenyl moieties as vanillyl surrogates, have been investigated as ligands for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Although lacking the metabolically problematic 4-hydroxy substituent on the A-region phenyl ring, the compounds retained substantial agonist potency. Indeed, the 3-methoxy-4-methylsulfonylaminophenyl analog (1) was modestly (2.5-fold) more potent than RTX, with an EC50 = 0.106 nM. Further, it resembled RTX in its kinetics and pattern of stimulation of the levels of intracellular calcium in individual cells, as revealed by imaging. Compound 1 displayed modestly enhanced in vitro stability in rat liver microsomes and in plasma, suggesting that it might be a pharmacokinetically more favorable surrogate of resiniferatoxin. Molecular modeling analyses with selected analogues provide evidence that the conformational differences could affect their binding affinities, especially for the ester versus amide at the B-region. 相似文献
892.
893.
Arlian LG Morgan MS Vyszenski-Moher DL Sharra D 《Experimental & applied acarology》2009,47(2):159-172
Many patients have sensitivities to multiple species of storage and house dust mites. It is not clear if this is because patients
have multiple sensitivities to species-specific mite allergens or if these mites share many cross-reacting allergens. Our
objective was to further define the cross-allergenicity between several species of storage and house dust mites using crossed-immunoelectrophoresis
(CIE), crossed-radioimmunoelectrophoresis (CRIE), immunoblotting, and ELISA. CIE and CRIE reactions revealed that storage
mites shared two cross-antigenic molecules and one of these bound IgE in a serum pool from mite allergic patients. Antibody
in anti-sera built to each species of mite recognized many SDS–PAGE resolved proteins of other mite species and this suggested
the potential for other cross-reactive allergens. Among patient sera, IgE bound to many different proteins but few had IgE
that bound to a protein with common molecular weights across the mite species and this suggested mostly species-specific allergens.
Antiserum built to each mite species precipitated one protein in shrimp extracts that bound anti-Der p 10 (tropomyosin) and
IgE in the serum pool. Anti-Der p 10 showed strong binding to shrimp tropomyosin but very little to any of the mite proteins.
ELISA showed the mite extracts contained very little tropomyosin. The storage and dust mites investigated contain mostly species-specific
allergens and very small amounts of the pan-allergen tropomyosin compared to shrimp and snail. 相似文献
894.
895.
896.
Charles A. Flentge John T. Randolph Peggy P. Huang Larry L. Klein Kennan C. Marsh John E. Harlan Dale J. Kempf 《Bioorganic & medicinal chemistry letters》2009,19(18):5444-5448
The HIV protease inhibitor ritonavir (RTV) is also a potent inhibitor of the metabolizing enzyme cytochrome P450 3A (CYP3A) and is clinically useful in HIV therapy in its ability to enhance human plasma levels of other HIV protease inhibitors (PIs). A novel series of CYP3A inhibitors was designed around the structural elements of RTV believed to be important to CYP3A inhibition, with general design features being the attachment of groups that mimic the P2–P3 segment of RTV to a soluble core. Several analogs were found to strongly enhance plasma levels of lopinavir (LPV), including 8, which compares favorably with RTV in the same model. Interestingly, an inverse correlation between in vitro inhibition of CYP3A and elevation of LPV was observed. The compounds described in this study may be useful for enhancing the pharmacokinetics of drugs that are metabolized by CYP3A. 相似文献
897.
Agrobacterium tumefaciens and Agrobacterium rhizogenes are related pathogens that cause crown gall and hairy root diseases, which result from integration and expression of bacterial genes in the plant genome. Single-stranded DNA (T strands) and virulence proteins are translocated into plant cells by a type IV secretion system. VirD2 nicks a specific DNA sequence, attaches to the 5′ end, and pilots the DNA into plant cells. A. tumefaciens translocates single-stranded DNA-binding protein VirE2 into plant cells where it likely binds T strands and may aid in targeting them into the nucleus. Although some A. rhizogenes strains lack VirE2, they transfer T strands efficiently due to the GALLS gene, which complements an A. tumefaciens virE2 mutant for tumor formation. Unlike VirE2, full-length GALLS (GALLS-FL) contains ATP-binding and helicase motifs similar to those in TraA, a strand transferase involved in conjugation. GALLS-FL and VirE2 contain nuclear localization signals (NLS) and secretion signals. Mutations in any of these domains abolish the ability of the GALLS gene to substitute for virE2. Here, we show that the GALLS gene encodes two proteins from one open reading frame: GALLS-FL and a protein comprised of the C-terminal domain, which initiates at an internal in-frame start codon. On some hosts, both GALLS proteins were required to substitute for VirE2. GALLS-FL tagged with yellow fluorescent protein localized to the nucleus of tobacco cells in an NLS-dependent manner. In plant cells, the GALLS proteins interacted with themselves, VirD2, and each other. VirD2 interacted with GALLS-FL and localized inside the nucleus, where its predicted helicase activity may pull T strands into the nucleus. 相似文献
898.
Brian L. Lee Xiuju Li Yongsheng Liu Brian D. Sykes Larry Fliegel 《The Journal of biological chemistry》2009,284(17):11546-11556
The Na+/H+ exchanger isoform 1 is a ubiquitously
expressed integral membrane protein that regulates intracellular pH in mammals
by extruding an intracellular H+ in exchange for one extracellular
Na+. We characterized structural and functional aspects of the
critical transmembrane (TM) segment XI (residues 449-470) by using cysteine
scanning mutagenesis and high resolution NMR. Each residue of TM XI was
mutated to cysteine in the background of the cysteine-less protein and the
sensitivity to water-soluble sulfhydryl reactive compounds MTSET
((2-(trimethylammonium) ethyl)methanethiosulfonate) and MTSES
((2-sulfonatoethyl) methanethiosulfonate) was determined for those residues
with at least moderate activity remaining. Of the residues tested, only
proteins with mutations L457C, I461C, and L465C were inhibited by MTSET. The
activity of the L465C mutant was almost completely eliminated, whereas that of
the L457C and I461C mutants was partially affected. The structure of a peptide
representing TM XI (residues Lys447-Lys472) was
determined using high resolution NMR spectroscopy in dodecylphosphocholine
micelles. The structure consisted of helical regions between
Asp447-Tyr454 and Phe460-Lys471 at
the N and C termini of the peptide, respectively, connected by a region with
poorly defined, irregular structure consisting of residues
Gly455-Gly459. TM XI of NHE1 had a structural similarity
to TM XI of the Escherichia coli Na+/H+
exchanger NhaA. The results suggest that TM XI is a discontinuous helix, with
residue Leu465 contributing to the pore.The mammalian Na+/H+ exchanger isoform 1
(NHE1)4 is a
ubiquitous integral membrane protein that regulates intracellular pH. It
mediates removal of a single intracellular proton in exchange for an
extracellular sodium ion (1).
NHE1 has many functions aside from protection of cells from intracellular
acidification (2). It promotes
cell growth and differentiation
(3), regulates sodium fluxes
and cell volume after challenge by osmotic shrinkage
(4), and has been demonstrated
to be involved in modulating cell motility
(5). In addition its activity
is important in invasiveness of neoplastic breast cancer cells
(6). NHE1 also plays critical
roles in heart disease. It has a contributing role in heart hypertrophy and in
the damage that occurs during ischemia and reperfusion. Inhibition of NHE1
with Na+/H+ exchanger inhibitors protects the myocardium
during various disease states
(7-10).NHE1 is composed of two general regions, an N-terminal membrane domain of
∼500 amino acids and a C-terminal regulatory domain of ∼315 amino
acids (1,
8). The membrane domain is
responsible for ion movement and an analysis of topology by cysteine scanning
accessibility suggested it has 3 membrane-associated segments and 12 integral
transmembrane segments (11)
(Fig. 1A). The
mechanism of transport of the membrane domain is of great interest both from a
scientific viewpoint and in the design of improved NHE1 inhibitors that may be
necessary for clinical use (1).
In this regard, we have recently characterized the functionally important
residues and the structure of both TM IV and TM VII. Prolines 167 and 168 of
TM IV were critical to NHE1 function
(12) and cysteine-scanning
mutagenesis was used to show that Phe161 is a pore lining residue
critical to transport. Analysis of the structure of TM IV showed that TM IV is
composed of one region of β-turns, an extended middle region including
Pro167-Pro168, and a helical region
(13). TM VII was much more
typical of a transmembrane helix although it was interrupted with a break in
the helix at the functionally critical residues
Gly261-Glu262
(14).Open in a separate windowFIGURE 1.Models of the Na+/H+ exchanger.
A, simplified topological model of the transmembrane domain of the
NHE1 isoform of the Na+/H+ exchanger as described
earlier (11). EL,
extracellular loop; IL, intracellular loop. B, model of amino acids
present in TM XI.Another important TM segment of the Na+/H+ exchanger
is TM XI (Fig. 1B).
Several different lines of evidence have suggested that it is critical to NHE1
function. A recent study generated chimeras of NHE1 from various species and
found that a region including TM XI was important in determining NHE1
inhibitor sensitivity (15).
More specifically, mutagenesis of several amino acids of TM XI has shown that
it is likely involved in either ion transport or proper targeting to the
plasma membrane. Two mutants in TM XI, Y454C and R458C, are retained in the
endoplasmic reticulum (16). In
addition, mutation of Gly455 and Gly456 in TM XI shift
the pHi dependence of the exchanger to the alkaline side,
whereas mutation of Arg440 in intracellular loop 5 at the
N-terminal end of TM XI shifts the pHi dependence to make
it more acidic (17,
18). Also, the structure of
the bacterial Na+/H+ exchanger NhaA has been elucidated.
Both TM IV and TM XI play a critical role forming an assembly that cross, with
each being a helix, an extended polypeptide and a short helix
(19). We found that TM IV of
NHE1 has a similar structure and function to that of TM IV of NhaA
(2,
13), leaving open the
possibility that TM XI of NHE1 is also similar in structure and function to TM
XI of NhaA.For these reasons, we undertook a systematic examination of the structural
and functional aspects of TM XI of the NHE1 isoform of the
Na+/H+ exchanger. The sequence of human TM XI of NHE1 is
449QFIIAYGGLRGAIAFSLGYLLD470. In this study we use
cysteine scanning mutagenesis and site-specific mutagenesis to identify and
characterize critical pore lining residues of the protein. We also use nuclear
magnetic resonance (NMR) spectroscopy to characterize the structure of a
synthetic peptide representing TM XI in dodecylphosphocholine (DPC) micelles.
Evidence has suggested that TM segments of membrane proteins possess all the
structural information required to form their higher order structures in their
amino acid sequence (20). This
has been demonstrated in earlier studies on membrane protein segments such as
the cystic fibrosis transmembrane conductance regulator
(21), a fungal
G-protein-coupled receptor
(22), bacteriorhodopsin
(23,
24), and rhodopsin
(25), where it was shown that
isolated TM segments from membrane proteins had structures in good agreement
with the segments of the entire protein. Also, the use of DPC micelles has
been shown to be an excellent membrane mimetic environment for these studies
(26,
27). Our study identifies
Leu465 as contributing to the pore of the protein and shows that
the structure of TM XI consists of two helices corresponding to
Asp447-Tyr454 and Phe460-Lys471 at
the N and C termini, respectively, connected by a flexible region at residues
455-459. The structure of TM XI was similar to the x-ray structure of TM XI of
NhaA. 相似文献
899.
Alexandre Chigaev Anna Waller Or Amit Liliana Halip Cristian G. Bologa Larry A. Sklar 《The Journal of biological chemistry》2009,284(21):14337-14346
Integrins are heterodimeric adhesion receptors that regulate immune cell
adhesion. Integrin-dependent adhesion is controlled by multiple conformational
states that include states with different affinity to the ligand, states with
various degrees of molecule unbending, and others. Affinity change and
molecule unbending play major roles in the regulation of cell adhesion. The
relationship between different conformational states of the integrin is
unclear. Here we have used conformationally sensitive antibodies and a small
LDV-containing ligand to study the role of the inside-out signaling through
formyl peptide receptor and CXCR4 in the regulation of
α4β1 integrin conformation. We found that in
the absence of ligand, activation by formyl peptide or SDF-1 did not result in
a significant exposure of HUTS-21 epitope. Occupancy of the ligand binding
pocket without cell activation was sufficient to induce epitope exposure.
EC50 for HUTS-21 binding in the presence of LDV was identical to a
previously reported ligand equilibrium dissociation constant at rest and after
activation. Furthermore, the rate of HUTS-21 binding was also related to the
VLA-4 activation state even at saturating ligand concentration. We propose
that the unbending of the integrin molecule after guanine nucleotide-binding
protein-coupled receptor-induced signaling accounts for the enhanced rate of
HUTS-21 binding. Taken together, current results support the existence of
multiple conformational states independently regulated by both inside-out
signaling and ligand binding. Our data suggest that VLA-4 integrin hybrid
domain movement does not depend on the affinity state of the ligand binding
pocket.In the bloodstream circulating leukocytes respond to inflammatory signals
by rapid changes of cell adhesive properties. These include cell tethering,
rolling, arrest, and firm adhesion, all of which are well described steps of
leukocyte recruitment to the sites of inflammation
(1). Leukocyte arrest and firm
adhesion are mediated exclusively by integrin receptors
(2). At the same time integrins
can also mediate tethering and rolling
(3). These largely diverse cell
adhesive properties are achieved by sophisticated conformational regulation;
multiple states of the same molecule with different affinity for its ligand
and different degrees of molecular unbending are attributed to various types
of “cellular behavior.” It is proposed that the low affinity bent
state translates into a non-adhesive resting cell, the low affinity unbent or
extended state of integrin results in cell rolling, and the high affinity
state promotes cell arrest (4,
5). However, the exact sequence
of conformational events and the relationship between integrin conformational
and functional activity remain key questions
(6).Integrin conformation is regulated through G-protein-coupled receptors by a
signaling pathway which is initiated by ligand binding to a
GPCR,3 propagated
inside the cell, and results in the binding of signaling proteins (such as
talin and others) to cytoplasmic domains of integrin subunits. This binding
leads to a separation of the integrin cytoplasmic domains and inside-out
activation (6). Chemokines
(chemotactic cytokines) as well as “classical” chemoattractants
(such as formyl peptide) preferentially signal through heterotrimeric
G-proteins coupled to the Gαi subunit
(1). Activation by these
ligands results in up-regulation of integrin affinity and/or conformational
unbending (extension) of the integrin molecule. These conformational changes
lead to cell arrest and firm adhesion. G-protein receptors coupled to
Gαs-coupled subunit (adenylyl cyclase/cAMP signaling pathway)
can actively down-regulate the affinity state of the ligand binding pocket
without changing integrin conformational unbending. This provides an
anti-adhesive signal and results in cell de-adhesion
(7). Thus, interaction of
multiple G-protein-coupled receptors on a single cell creates a plethora of
conformational states. Understanding of the relationship between inside-out
signaling through GPCRs and integrin conformational regulation will provide
valuable insight into the dynamic regulation of cell adhesion.One technique to study conformational changes of integrins uses
conformationally sensitive mAbs that bind to epitopes which are hidden in one
conformation and exposed under certain conditions. Lately, it has been
accepted that integrins exhibit two major conformations, resting and
activated. A number of mAbs for “activated” integrins have been
described, and the epitopes have been mapped. Together with mapping of these
epitopes into three-dimensional structures of integrin
(8), epitope exposure can
provide helpful information about integrin conformational changes upon
signaling. Moreover, because integrin inside-out activation through different
signaling pathways can result in different activation states, the use of
previously mapped mAbs can help dissect conformational changes upon
activation.Although it is clear that inside-out activation results in a conformational
rearrangement of the integrin molecule, the relationship between affinity
state of the ligand binding pocket and overall molecule conformation is still
debated. Currently, two contrasting models of integrin inside-out integrin
activation are described. The “switchblade” model implies that an
open head structure with swung-out β-hybrid domain represents the high
(or at least intermediate) affinity state. A feature of this model is that
integrin extension provides space for hybrid domain swing. The
“deadbolt” model proposes that the movement of β-hybrid
domain is not related to the inside-out signal. Ligand binding by itself can
provide the energy for the hybrid domain swing out (for details, see Ref.
9 and references therein).
Because these two models assign different roles to the hybrid domain motion,
we evaluated the exposure of VLA-4 hybrid domain epitopes upon activation
through two Gαi-coupled GPCRs (FPR and CXCR4) and ligand
binding using the conformationally sensitive HUTS-21 mAb with an epitope
mapped to the hybrid domain of β1-integrin
(10).We found that contrary to previous reports, where these mAbs were reported
to bind or used for the detection of activated integrin
(10–13),
formyl peptide or SDF-1 treatment alone did not result in any significant
exposure of HUTS-21 epitope despite the fact that the VLA-4 affinity
up-regulation was detected in parallel on the same batch of cells.
Quantitative analysis of mAb binding in real time on live cells suggests that
for both the low (resting) and high affinity (induced by inside-out pathway)
states, occupancy of the ligand binding pocket rather than inside-out
signaling by itself causes the conformational change. Thus, these data support
the idea that the hybrid domain movement, which results in the exposure of the
mAb epitope, and the high affinity state of the binding pocket are regulated
separately and independently of each other, a feature of the deadbolt model of
inside-out activation. 相似文献
900.
Matthew J. Betzenhauser Larry E. Wagner II Hyung Seo Park David I. Yule 《The Journal of biological chemistry》2009,284(24):16156-16163
ATP is known to increase the activity of the type-1 inositol 1,4,5-trisphosphate receptor (InsP3R1). This effect is attributed to the binding of ATP to glycine rich Walker A-type motifs present in the regulatory domain of the receptor. Only two such motifs are present in neuronal S2+ splice variant of InsP3R1 and are designated the ATPA and ATPB sites. The ATPA site is unique to InsP3R1, and the ATPB site is conserved among all three InsP3R isoforms. Despite the fact that both the ATPA and ATPB sites are known to bind ATP, the relative contribution of these two sites to the enhancing effects of ATP on InsP3R1 function is not known. We report here a mutational analysis of the ATPA and ATPB sites and conclude neither of these sites is required for ATP modulation of InsP3R1. ATP augmented InsP3-induced Ca2+ release from permeabilized cells expressing wild type and ATP-binding site-deficient InsP3R1. Similarly, ATP increased the single channel open probability of the mutated InsP3R1 to the same extent as wild type. ATP likely exerts its effects on InsP3R1 channel function via a novel and as yet unidentified mechanism.Inositol 1,4,5-trisphosphate receptors (InsP3R)3 are a family of large, tetrameric, InsP3-gated cation channels. The three members of this family (InsP3R1, InsP3R2, and InsP3R3) are nearly ubiquitously expressed and are localized primarily to the endoplasmic reticulum (ER) membrane (1–3). Numerous hormones, neurotransmitters, and growth factors bind to receptors that stimulate phospholipase C-induced InsP3 production (4). InsP3 subsequently binds to the InsP3R and induces channel opening. This pathway represents a major mechanism for Ca2+ liberation from ER stores (5). All three InsP3R isoforms are dynamically regulated by cytosolic factors in addition to InsP3 (1). Ca2+ is perhaps the most important determinant of InsP3R activity besides InsP3 itself and is known to regulate InsP3R both positively and negatively (6). ATP, in concert with InsP3 and Ca2+, also regulates InsP3R as do numerous kinases, phosphatases, and protein-binding partners (7–10). This intricate network of regulation allows InsP3R activity to be finely tuned by the local cytosolic environment (9). As a result, InsP3-induced Ca2+ signals can exhibit a wide variety of spatial and temporal patterns, which likely allows Ca2+ to control many diverse cellular processes.Modulation of InsP3-induced Ca2+ release (IICR) by ATP and other nucleotides provides a direct link between intracellular Ca2+ signaling and the metabolic state of the cell. Metabolic fluctuations could, therefore, impact Ca2+ signaling in many cell types given that InsP3R are expressed in all cells (11, 12). Consistent with this, ATP has been shown to augment IICR in many diverse cell types including primary neurons (13), smooth muscle cells (14), and exocrine acinar cells (15) as well as in immortalized cell lines (16–18). The effects of ATP on InsP3R function do not require hydrolysis because non-hydrolyzable ATP analogues are as effective as ATP (7, 14). ATP is thought to bind to distinct regions in the central, coupling domain of the receptors and to facilitate channel opening (2, 19). ATP is not required for channel gating, but instead, increases InsP3R activity in an allosteric fashion by increasing the open probability of the channel in the presence of activating concentrations of InsP3 and Ca2+ (7, 8, 20).Despite a wealth of knowledge regarding the functional effects of ATP on InsP3R function, there is relatively little known about the molecular determinants of these actions. ATP is thought to exert effects on channel function by direct binding to glycine-rich regions containing the consensus sequence GXGXXG that are present in the receptors (2). These sequences were first proposed to be ATP-binding domains due to their similarity with Walker A motifs (21). The neuronal S2+ splice variant of InsP3R1 contains two such domains termed ATPA and ATPB. A third site, ATPC, is formed upon removal of the S2 splice site (2, 22). The ATPB site is conserved in InsP3R2 and InsP3R3, while the ATPA and ATPC sites are unique to InsP3R1. Our prior work examining the functional consequences of mutating these ATP-binding sites has yielded unexpected results. For example, mutating the ATPB site in InsP3R2 completely eliminated the enhancing effects of ATP on this isoform while mutating the analogous site in InsP3R3 failed to alter the effects of ATP (23). This indicated the presence of an additional locus for ATP modulation of InsP3R3. In addition, mutation of the ATPC in the S2− splice variant of InsP3R1 did not alter the ability of ATP to modulate Ca2+ release, but instead impaired the ability of protein kinase A to phosphorylate Ser-1755 of this isoform (22).The ATPA and ATPB sites in InsP3R1 were first identified as putative nucleotide-binding domains after the cloning of the full-length receptor (24). Early binding experiments with 8-azido-[α-32P]ATP established that ATP cross-linked with receptor purified from rat cerebellum at one site per receptor monomer (19). Later, more detailed, binding experiments on trypsinized recombinant rat InsP3R1 showed cross-linking of ATP to two distinct regions of the receptor that corresponded with the ATPA and ATPB sites (17). We and others (16, 22, 23) have also reported the binding of ATP analogues to purified GST fusions of small regions of InsP3R1 surrounding the ATPA and ATPB sites. It is widely accepted, in the context of the sequence similarity to Walker A motifs and biochemical data, that the ATPA and ATPB sites are the loci where ATP exerts its positive functional effects on InsP3R1 function (1–3, 16). Furthermore, the higher affinity of the ATPA site to ATP is thought to confer the higher sensitivity of InsP3R1 to ATP versus InsP3R3, which contains the ATPB site exclusively (25, 26). The purpose of this study, therefore, was to examine the contributions of the ATPA and ATPB sites to ATP modulation of the S2+ splice variant of InsP3R1. We compared the effects of ATP on InsP3R1 and on ATP-binding site mutated InsP3R1 using detailed functional analyses in permeabilized cells and in single channel recordings. Here we report that InsP3R1 is similar to InsP3R3 in that ATP modulates IICR even at maximal InsP3 concentrations and that neither the ATPA nor the ATPB site is required for this effect. 相似文献