scholarly journals Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex

2014 ◽  
Vol 70 (2) ◽  
pp. 451-460 ◽  
Author(s):  
Jacob Lauwring Andersen ◽  
Tenna Juul Schrøder ◽  
Søren Christensen ◽  
Dorthe Strandbygård ◽  
Lone Tjener Pallesen ◽  
...  
Keyword(s):  
Small Molecule ◽  
Binding Mode ◽  
Membrane Glycoprotein ◽  
Type I ◽  
Ligand Complex ◽  
Neuronal Viability ◽  
The Central Nervous System ◽  
Vacuolar Protein ◽  
Small Molecule Ligand

Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin–AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7 Å resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.

scholarly journals Protein–ligand complex structure from serial femtosecond crystallography using soaked thermolysin microcrystals and comparison with structures from synchrotron radiation

2017 ◽  
Vol 73 (8) ◽  
pp. 702-709 ◽  
Author(s):  
Hisashi Naitow ◽  
Yoshinori Matsuura ◽  
Kensuke Tono ◽  
Yasumasa Joti ◽  
Takashi Kameshima ◽  
...  
Keyword(s):  
Synchrotron Radiation ◽  
Room Temperature ◽  
Complex Structure ◽  
Binding Mode ◽  
Ligand Complex ◽  
X Ray ◽  
Cell Parameters ◽  
Serial Femtosecond Crystallography ◽  
Small Molecule Ligand

Serial femtosecond crystallography (SFX) with an X-ray free-electron laser is used for the structural determination of proteins from a large number of microcrystals at room temperature. To examine the feasibility of pharmaceutical applications of SFX, a ligand-soaking experiment using thermolysin microcrystals has been performed using SFX. The results were compared with those from a conventional experiment with synchrotron radiation (SR) at 100 K. A protein–ligand complex structure was successfully obtained from an SFX experiment using microcrystals soaked with a small-molecule ligand; both oil-based and water-based crystal carriers gave essentially the same results. In a comparison of the SFX and SR structures, clear differences were observed in the unit-cell parameters, in the alternate conformation of side chains, in the degree of water coordination and in the ligand-binding mode.

scholarly journals Evidence vs Expectations: How to validate your ligand in a protein structure

2014 ◽  
Vol 70 (a1) ◽  
pp. C1479-C1479
Author(s):  
Edwin Pozharski
Keyword(s):  
Structural Biology ◽  
Complex Structure ◽  
Structural Data ◽  
High Expectation ◽  
Ligand Complex ◽  
Ligand Interaction ◽  
Protein Ligand Interaction ◽  
Experimental Findings ◽  
Small Molecule Ligand

Determination of a protein-ligand complex structure is essential in many areas of structural biology. Details of the interactions between protein and a small molecule ligand often represent major findings from a crystal structure. Thorough validation of interpretation of such structural data is particularly important given high expectation of confirming prior experimental findings regarding targeted protein-ligand interaction. Modern methods of ligand validation are discussed and illustrated.

Binding Mode Determination of Benzimidazole Inhibitors of the Hepatitis C Virus RNA Polymerase by a Structure and Dynamics Strategy

2004 ◽  
Vol 116 (33) ◽  
pp. 4406-4411 ◽  
Author(s):  
Steven R. LaPlante ◽  
Araz Jakalian ◽  
Norman Aubry ◽  
Yves Bousquet ◽  
Jean-Marie Ferland ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Binding Mode ◽  
Hepatitis C Virus Rna ◽  
Structure And Dynamics ◽  
Virus Rna

scholarly journals Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

2017 ◽  
Vol 114 (33) ◽  
pp. E6942-E6951 ◽  
Author(s):  
Genevieve E. Lind ◽  
Tung-Chung Mou ◽  
Lucia Tamborini ◽  
Martin G. Pomper ◽  
Carlo De Micheli ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Binding Affinity ◽  
Binding Mode ◽  
Structural Basis ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Glutamate Binding ◽  
Subunit Interface ◽  
The Central Nervous System ◽  
Contact Residues

NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.

scholarly journals Bioanalysis of small-molecule drugs in nasal and paranasal tissues and secretions: Current status and perspectives

2012 ◽  
Vol 10 (3) ◽  
pp. 686-702
Author(s):  
Ana Serralheiro ◽  
Gilberto Alves ◽  
Amílcar Falcão
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Small Molecule ◽  
Intranasal Administration ◽  
Quantitative Measurement ◽  
Current Status ◽  
Small Molecule Drugs ◽  
Development And Validation ◽  
Liquid Chromatographic

AbstractOver the last years, interest in intranasal administration as an alternative and promising route for the delivery of drugs withlocal, systemic, and even central nervous system action has tremendously increased. Accordingly, understanding of the propertiesand characteristics of the nasal cavity as well as the biodisposition processes of drugs into the nasal compartments is acquiringa significant prominence in the field of pharmacology. In this context, the development and validation of bioanalytical methodologies for the quantitative measurement of drugs and their metabolites in nasal and paranasal tissues and/or secretions is of the utmostimportance. However, currently, information concerning bioanalysis of drugs in nasal and paranasal tissues and/or secretionsis scattered. This review aims to provide a valuable overview of the methodologies that have been used for the collectionand preparation of nasal and paranasal samples with special emphasis placed on the review of liquid chromatographic methodsemployed for the quantitative determination of small-molecule drugs and their metabolites in such specimens.

scholarly journals Human Cytomegalovirus Open Reading Frame TRL11/IRL11 Encodes an Immunoglobulin G Fc-Binding Protein

2001 ◽  
Vol 75 (22) ◽  
pp. 11218-11221 ◽  
Author(s):  
Brendan N. Lilley ◽  
Hidde L. Ploegh ◽  
Rebecca S. Tirabassi
Keyword(s):  
Human Cytomegalovirus ◽  
Immunoglobulin G ◽  
Binding Protein ◽  
Fc Receptors ◽  
Binding Activity ◽  
Open Reading Frame ◽  
Membrane Glycoprotein ◽  
Type I ◽  
Reading Frame

ABSTRACT Several herpesviruses encode Fc receptors that may play a role in preventing antibody-mediated clearance of the virus in vivo. Human cytomegalovirus (HCMV) induces an Fc-binding activity in cells upon infection, but the gene that encodes this Fc-binding protein has not been identified. Here, we demonstrate that the HCMV AD169 open reading frame TRL11 and its identical copy, IRL11, encode a type I membrane glycoprotein that possesses IgG Fc-binding capabilities.

CHRONIC LEAD ENCEPHALOPATHY

PEDIATRICS ◽  
1960 ◽  
Vol 25 (2) ◽  
pp. 309-315
Author(s):  
Harry H. White ◽  
Fred D. Fowler
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Pediatric Patients ◽  
Early Recognition ◽  
Central Nervous System Involvement ◽  
Fast Screening ◽  
The Central Nervous System ◽  
Lead Encephalopathy ◽  
Urinary Coproporphyrin

Chronic lead encephalopathy must be considered in the differential diagnosis of pediatric patients who present with manifestations of schizophrenia, behavior disorders or degenerative diseases of the central nervous system. Determination of urinary coproporphyrin is a simple, fast screening procedure applicable to office practice. The prognosis for normal mental development following encephalopathy is poor. It is hoped that early recognition of the more subtle signs of central nervous system involvement will allow treatment to be instituted soon enough to prevent the crippling mental deterioration which is so often a sequela of lead poisoning.

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