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Receptor Recognition (receptor + recognition)
Selected AbstractsImmune modulation of HLA-G dimer in maternal-fetal interfaceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007Kimiko Kuroki Abstract HLA-G is a non-classical human MHC class I molecule, which has several characteristics distinct from classical MHC, such as low polymorphism and restricted tissue distribution. HLA-G is expressed on placenta, thymus and some tumors. At the maternal-fetal interface, trophoblasts do not express major classical MHC class I molecules (MHCI), HLA-A and -B, to prevent normal T cell responses. Instead, HLA-G is expressed and can suppress a wide range of immune responses by binding to inhibitory immune cell surface receptors, such as leukocyte Ig-like receptor (LILR) B1 and LILRB2. HLA-G exists in various forms, including ,2m-associated or -free disulfide-linked dimers that can be expressed either at the cell surface or in soluble form. However, until recently the physiological role of these different molecular forms has been unclear. In this issue of the European Journal of Immunology, one article demonstrates that the disulfide-linked homodimer of ,2m-associated HLA-G is the major fraction expressed by trophoblast cells. The HLA-G dimer modulates the function of LILRB1-expressing antigen-presenting cells by principally binding to LILRB1. On the other hand, another recent report showed that ,2m-free disulfide-linked HLA-G dimers are produced by villous cytotrophoblast cells. Taken together, these results provide strong evidence in support of the hypothesis that HLA-G dimers play a role in immune suppression at the maternal-fetal interface. Further in-depth investigation will help to clarify the precise mechanism of HLA-G receptor recognition and signaling in vivo and the role of these interactions in successful reproduction. See accompanying article: http://dx.doi.org/10.1002/eji.200737089 [source] Sequential model of phage PRD1 DNA delivery: active involvement of the viral membraneMOLECULAR MICROBIOLOGY, Issue 5 2002A. Marika Grahn Summary DNA translocation across the barriers of recipient cells is not well understood. Viral DNA delivery mechanisms offer an opportunity to obtain useful information in systems in which the process can be arrested to a number of stages. PRD1 is an icosahedral double-stranded (ds)DNA bacterial virus with an internal membrane. It is an atypical dsDNA phage, as any of the vertex spikes can be used for receptor recognition. In this report, we dissect the PRD1 DNA entry into a number of steps: (i) outer membrane (OM) penetration; (ii) peptidoglycan digestion; (iii) cytoplasmic membrane (CM) penetration; and (iv) DNA translocation. We present a model for PRD1 DNA entry proposing that the initial stage of entry is powered by the pressure build-up during DNA packaging. The viral protein P11 is shown to function as the first DNA delivery protein needed to penetrate the OM. We also report a DNA translocation machinery composed of at least three viral integral membrane proteins, P14, P18 and P32. [source] Crystal structure of a dimeric form of streptococcal pyrogenic exotoxin A (SpeA1)PROTEIN SCIENCE, Issue 9 2004Matthew D. Baker Abstract Streptococcal pyrogenic exotoxin A (SpeA1) is a bacterial superantigen associated with scarlet fever and streptococcal toxic shock syndrome (STSS). SpeA1 is found in both monomeric and dimeric forms, and previous work suggested that the dimer results from an intermolecular disulfide bond between the cysteines at positions 90 of each monomer. Here, we present the crystal structure of the dimeric form of SpeA1. The toxin crystallizes in the orthorhombic space group P212121, with two dimers in the crystallographic asymmetric unit. The final structure has a crystallographic R-factor of 21.52% for 7248 protein atoms, 136 water molecules, and 4 zinc atoms (one zinc atom per molecule). The implications of SpeA1 dimer on MHC class II and T-cell receptor recognition are discussed. [source] Specific GABAA agonists and partial agonistsTHE CHEMICAL RECORD, Issue 6 2002Povl Krogsgaard-Larsen Abstract The GABAA receptor system is implicated in a number of neurological and psychiatric diseases, making GABAA receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the hetero-pentameric GABAA receptor complex, reflecting the very strict structural requirements for GABAA receptor recognition and activation. Within the series of compounds showing agonist activity at the GABAA receptor site that have been developed, most of the ligands are structurally derived from the GABAA agonists muscimol, THIP, or isoguvacine, which we developed in the initial stages of the project. Using recombinant GABAA receptors, functional selectivity was demonstrated for a number of compounds, including THIP, showing highly subunit-dependent potency and maximal response. In light of the interest in partial GABAA receptor agonists as potential therapeutics, structure,activity studies of a number of analogs of 4-PIOL, a low-efficacy partial GABAA agonist derived from THIP, have been performed. In this connection, a series of GABAA ligands has been developed that exhibit pharmacological profiles from moderately potent low-efficacy partial GABAA agonist activity to potent and selective antagonist effects. Very little information is available on direct-acting GABAA receptor agonists in clinical studies. However, the results of clinical studies on the effect of the partial GABAA agonist THIP on human sleep patterns show that the functional consequences of a direct-acting agonist are different from those seen after the administration of GABAA receptor modulators, such as benzodiazepines and barbiturates. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc., Chem Rec 2: 419,430; 2002: Published online in Wiley Interscience (www.interscience.wiley.com) DOI 10.1002/tcr.10040 [source] Two enantiomerically pure cyclic arenesulfonamide hydrochloride saltsACTA CRYSTALLOGRAPHICA SECTION C, Issue 2 2009Lionel Kiefer The crystal structures of N -[(1R)-1-(1-naphthyl)ethyl]-3,4-dihydro-2H -1,2-benzothiazin-4-aminium 1,1-dioxide chloride, C20H21N2O2S+·Cl,, (I), a six-membered cyclic sulfonamide, and (1R)- N -[(5,5-dioxo-6,7-dihydrodibenzo[d,f][1,2]thiazepin-7-yl)methyl]-1-(1-naphthyl)ethanaminium chloride, C26H25N2O2S+·Cl,, (II), a seven-membered cyclic sulfonamide, both representative of a novel family of agonists of the extracellular calcium sensing receptor (CaSR) of possible clinical importance, are reported. The known chirality of the naphthylethylamine precursor has enabled assignment of the absolute configuration of both compounds, which is crucial for the receptor recognition. The crystal structures, though different, reveal for these agonists a notable absence of intramolecular ,,, stacking between their respective aromatic groups. This suggests a common structural feature that allows CaSR agonists to be distinguished from antagonists, since in the latter, such interactions have been shown to be important. The connectivities between molecules in the crystal structures are also different, but both involve hydrogen bonding mediated by chloride ions as a common dominant feature. [source] Improved synthesis of 5-hydroxylysine (Hyl) derivatives,CHEMICAL BIOLOGY & DRUG DESIGN, Issue 2 2005M. Cudic Abstract:, The synthesis of 5-hydroxylysine (Hyl) derivatives for incorporation by solid-phase methodologies presents numerous challenges. Hyl readily undergoes intramolecular lactone formation, and protected intermediates often have poor solubilities. The goals of this work were twofold: first, develop a convenient method for the synthesis of O -protected Fmoc-Hyl; secondly, evaluate the efficiency of methods for the synthesis of O -glycosylated Fmoc-Hyl. The 5- O - tert -butyldimethylsilyl (TBDMS) fluoren-9-ylmethoxycarbonyl-Hyl (Fmoc-Hyl) derivative was conveniently prepared by the addition of tert -butyldimethylsilyl trifluoromethanesulfonate to copper-complexed Hyl[, - tert -butyloxycarbonyl (Boc)]. The complex was decomposed with Na+ Chelex resin and the Fmoc group added to the , -amino group. Fmoc-Hyl(, -Boc, O -TBDMS) was obtained in 67% overall yield and successfully used for the solid-phase syntheses of 3 Hyl-containing peptides. The preparation of Fmoc-Hyl[, -Boc, O -(2,3,4,6-tetra- O -acetyl- , - d -galactopyranosyl)] was compared for the thioglycoside, trichloroacetimidate and Koenigs,Knorr methods. The most efficient approach was found to be Koenigs,Knorr under inverse conditions, where Fmoc-Hyl(, -Boc)-OBzl and peracetylated galactosyl bromide were added to silver trifluoromethanesulfonate in 1,2-dichloroethane, resulting in a 45% isolated yield. Side-reactions that occurred during previously described preparations of glycosylated Hyl derivatives, such as lactone formation, loss of side-chain protecting groups, orthoester formation, or production of anomeric mixtures, were avoided here. Research on the enzymology of Lys hydroxylation and subsequent glycosylation, as well as the role of glycosylated Hyl in receptor recognition, will be greatly aided by the convenient and efficient synthetic methods developed here. [source] Incorporation of vinylogous scaffolds in the C-terminal tripeptide of substance PCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2004S. Claudel Abstract:, Glycine-9 and leucine-10 of substance P (SP) are critical for (NK)-1 receptor recognition and agonist activity. Pro,(Z)-CH=CH(CH3)-CONH)Leu (or Met) and Pro,((E) -CH=CH(CH3)-CONH)Leu (or Met) have been introduced in the sequence of SP, in order to restrict the conformational flexibility of the C-terminal tripeptide, Gly-Leu-Met-NH2, of SP. Pro,((Z) -CH=C(CH2CH(CH3)2)-CONH)Met-NH2, with an isobutyl substituent to mimic the Leu side-chain, was also incorporated in place of the C-terminal tripeptide. The substituted-SP analogs were tested for their affinity to human NK-1 receptor specific binding sites (NK-1M and NK-1m) and their potency to stimulate adenylate cyclase and phospholipase C in Chinese Hamster ovary (CHO) cells transfected with the human NK-1 receptor. The most potent SP analogs [Pro9,((Z)CH=C(CH3)CONH)Leu10]SP and [Pro9, ((E)CH=C(CH3)CONH)Leu10]SP, are about 100-fold less potent than SP on both binding sites and second messenger pathways. These vinylogous (Z) - or (E) -CH=C(CH3)- or (Z) -CH=C(CH2CH(CH3)2) moieties hamper the correct positioning of the C-terminal tripeptide of SP within both the NK-1M- and NK-1m-specific binding sites. The origin of these lower potencies is related either to an incorrect peptidic backbone conformation and/or an unfavorable receptor interaction of the methyl or isobutyl group. [source] Configurations of Nickel,Cyclam Antiviral Complexes and Protein RecognitionCHEMISTRY - A EUROPEAN JOURNAL, Issue 1 2007Tina M. Hunter Abstract Nickel(II),xylylbicyclam is a potent anti-HIV agent and binds strongly to the CXCR4 co-receptor. We have investigated configurational equilibria of NiII,cyclam derivatives, since these are important for receptor recognition. Crystallographic studies show that both trans and cis configurations are readily formed: [Ni(cyclam)(OAc)2],H2O adopts the trans -III configuration with axial monodentate acetates, as does [Ni(benzylcyclam)(NO3)2] with axial nitrate ligands, whereas [Ni(benzylcyclam)(OAc)](OAc),2,H2O has an unusual folded cis -V configuration with NiII coordination to bidentate acetate. UV/Vis and NMR studies show that the octahedral trans -III configuration slowly converts to square-planar trans -I in aqueous solution. For NiII,xylylbicyclam, a mixture of cis -V and trans -I configurations was detected in solution. X-ray diffraction studies showed that crystals of lysozyme soaked in NiII,cyclam or NiII2,xylylbicyclam contain two major binding sites, one involving NiII coordination to Asp101 and hydrophobic interactions between the cyclam ring and Trp62 and Trp63, and the second hydrophobic interactions with Trp123. For NiII,cyclam bound to Asp101, the cis -V configuration predominates. 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