Home About us Contact
|
Home About us Contact | ||
|
|
||
Ligand Recognition (ligand + recognition)
Selected AbstractsA comparative study of the asparagine-linked oligosaccharides on siglec-5, siglec-7 and siglec-8, expressed in a CHO cell line, and their contribution to ligand recognitionFEBS JOURNAL, Issue 5 2001Sylvie Freeman The siglecs (sialic acid-binding immunoglobulin-like lectins) mediate sialic acid-dependent cellular interactions and may in some cases signal through SH2-binding domains. In addition to the previously characterized siglecs, sialoadhesin, CD22, CD33 and myelin-associated glycoprotein, several new ones, siglec-5, siglec-7 and siglec-8, have recently been cloned. Although these novel receptors have generated considerable interest as therapeutic targets because of their expression pattern on immune cells, very little is known about how their lectin activity is regulated. Previous studies with sialoadhesin, CD22 and CD33 have shown that siglec glycosylation has significant effects on binding. To determine any differences in the glycan composition of siglec-5, siglec-7 and siglec-8 that may modify their function, we released and characterized the N-linked oligosaccharide distribution in these three glycoproteins. The glycan pools from siglec-5 and siglec-7 contained a larger proportion of sialylated and core-fucosylated biantennary, triantennary and tetra-antennary oligosaccharides, whereas the carbohydrate mixture released from siglec-8 is noticeably less sialylated and is more abundant in ,high-mannose'-type glycans. In addition, we show that, in contrast with CD22 and CD33, mutating the conserved potentially N-linked glycosylation site in the first domain has no effect on binding mediated by siglec-5 or siglec-7. [source] Probing the limits of molecular imprinting: strategies with a template of limited size and functionalityJOURNAL OF MOLECULAR RECOGNITION, Issue 1 2009Miruna Petcu Abstract A series of polymers molecularly imprinted with the general anaesthetic propofol were synthesized using both semi- and non-covalent approaches. The polymers were evaluated with respect to template rebinding in both aqueous and organic media. In aqueous media, the observed propofol binding in these polymer systems was largely hydrophobic and non-specific in nature. In non-polar solvents such as hexane, electrostatic (hydrogen bonding) interactions dominate resulting in some selectivity. The implication of these results, in conjunction with those obtained using structures of similar size in other studies, is that propofol, a template possessing limited functionality and size, appears to define the lower limit for template size and degree of functionalization that can be used for the creation of ligand-selective recognition sites in molecularly imprinted polymers. Furthermore, studies with alternative ligands indicate that the steric crowding of a ligand's functionality to the polymer contributes to the extent of polymer,ligand recognition. Copyright © 2008 John Wiley & Sons, Ltd. [source] Molecular dynamics simulation of human neurohypophyseal hormone receptors complexed with oxytocin,modeling of an activated stateJOURNAL OF PEPTIDE SCIENCE, Issue 3 2006Magdalena J., lusarz Abstract The neurohypophyseal hormone oxytocin (CYIQNCPLG-NH2, OT) is involved in the control of labor, secretion of milk and many social and behavioral functions via interaction with its receptors (OTR) located in the uterus, mammary glands and peripheral tissues, respectively. In this paper we propose the interactions responsible for OT binding and selectivity to OTR versus vasopressin ([F3,R8]OT, AVP) receptors: V1aR and V2R, all three belonging to the Class A G protein-coupled receptors (GPCRs). Three-dimensional models of the activated receptors were constructed using a multiple sequence alignment and the activated rhodopsin,transducin (MII,Gt) prototype [,lusarz and Ciarkowski, 2004] as a template. The 1 ns unconstrained molecular dynamics (MD) of three pairs of receptor,OT complexes (two complexes per each receptor) immersed in the fully hydrated 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphatidylcholine (POPC) lipid bilayer was conducted in the AMBER 7.0 force field. The relaxed models of ligand,receptor complexes were used to identify the putative binding sites of OT. The stabilizing interactions with conserved Gln residues in all complexes were identified. The nonconserved hydrophobic residues were proposed as responsible for OTR,OT selectivity and ligand recognition. These results provide guidelines for experimental site-directed mutagenesis and if confirmed, they may be helpful in designing new selective OT analogs with both agonistic or antagonistic properties. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd. [source] Integrins, cations and ligands: making the connectionJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 7 2003J-P. Xiong Summary., Integrins are cell adhesion receptors that couple extracellular divalent cation-dependent recognition events with intracellular mechanical and biochemical responses and vice versa, thus affecting every function of nucleated cells. The structural basis of this bidirectional signaling and its dependency on cations has been the focus of intensive study over the past three decades. Significant progress made recently in elucidating the three-dimensional structure of the extracellular and cytoplasmic segments of integrins is giving valuable new insights into the tertiary and quaternary changes that underlie activation, ligand recognition and signaling by these receptors. [source] A new crystal form of human tear lipocalin reveals high flexibility in the loop region and induced fit in the ligand cavityACTA CRYSTALLOGRAPHICA SECTION D, Issue 10 2009Daniel A. Breustedt Tear lipocalin (TLC) with the bound artificial ligand 1,4-butanediol has been crystallized in space group P21 with four protein molecules in the asymmetric unit and its X-ray structure has been solved at 2.6,Å resolution. TLC is a member of the lipocalin family that binds ligands with diverse chemical structures, such as fatty acids, phospholipids and cholesterol as well as microbial siderophores and the antibiotic rifampin. Previous X-ray structural analysis of apo TLC crystallized in space group C2 revealed a rather large bifurcated ligand pocket and a partially disordered loop region at the entrace to the cavity. Analysis of the P21 crystal form uncovered major conformational changes (i) in ,-strands B, C and D, (ii) in loops 1, 2 and 4 at the open end of the ,-barrel and (iii) in the extended C-terminal segment, which is attached to the ,-barrel via a disulfide bridge. The structural comparison indicates high conformational plasticity of the loop region as well as of deeper parts of the ligand pocket, thus allowing adaptation to ligands that differ vastly in size and shape. This illustrates a mechanism for promiscuity in ligand recognition which may also be relevant for some other physiologically important members of the lipocalin protein family. [source] Structure of 3(17),-hydroxysteroid dehydrogenase (AKR1C21) holoenzyme from an orthorhombic crystal form: an insight into the bifunctionality of the enzymeACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 10 2007Urmi Dhagat Mouse 3(17),-hydroxysteroid dehydrogenase (AKR1C21) is a bifunctional enzyme that catalyses the oxidoreduction of the 3- and 17-hydroxy/keto groups of steroid substrates such as oestrogens, androgens and neurosteroids. The structure of the AKR1C21,NADPH binary complex was determined from an orthorhombic crystal belonging to space group P212121 at a resolution of 1.8,Å. In order to identify the factors responsible for the bifunctionality of AKR1C21, three steroid substrates including a 17-keto steroid, a 3-keto steroid and a 3,-hydroxysteroid were docked into the substrate-binding cavity. Models of the enzyme,coenzyme,substrate complexes suggest that Lys31, Gly225 and Gly226 are important for ligand recognition and orientation in the active site. [source] Molecular Dynamics Simulations of Na+/Cl, -Dependent Neurotransmitter Transporters in a Membrane-Aqueous SystemCHEMMEDCHEM, Issue 6 2007Anne Marie Jørgensen Abstract We have performed molecular dynamics simulations of a homology model of the human serotonin transporter (hSERT) in a membrane environment and in complex with either the natural substrate 5-HT or the selective serotonin reuptake inhibitor escitalopram. We have also included a transporter homologue, the Aquifex aeolicus leucine transporter (LeuT), in our study to evaluate the applicability of a simple and computationally attractive membrane system. Fluctuations in LeuT extracted from simulations are in good agreement with crystallographic B factors. Furthermore, key interactions identified in the X-ray structure of LeuT are maintained throughout the simulations indicating that our simple membrane system is suitable for studying the transmembrane protein hSERT in complex with 5-HT or escitalopram. For these transporter complexes, only relatively small fluctuations are observed in the ligand-binding cleft. Specific interactions responsible for ligand recognition, are identified in the hSERT,5HT and hSERT,escitalopram complexes. Our findings are in good agreement with predictions from mutagenesis studies. [source] | ||||||||||