scholarly journals Conserved Ca2+-antagonist-binding properties and putative folding structure of a recombinant high-affinity dihydropyridine-binding domain

2000 ◽  
Vol 347 (3) ◽  
pp. 829-836 ◽  
Author(s):  
Irene HUBER ◽  
Edwin WAPPL ◽  
Alexander HERZOG ◽  
Jörg MITTERDORFER ◽  
Hartmut GLOSSMANN ◽  
...  
Keyword(s):  
Dissociation Constants ◽  
Three Dimensional ◽  
Structural Data ◽  
Binding Pocket ◽  
K Channel ◽  
Interaction Domain ◽  
Ki 67 ◽  
Reasonable Approach ◽  
Binding Residues ◽  
Ca2 Channels

Sensitivity to 1,4-dihydropyridines (DHPs) can be transferred from L-type (α1C) to non-L-type (α1A) Ca2+ channel α1 subunits by the mutation of nine pore-associated non-conserved amino acid residues, yielding mutant α1ADHP. To determine whether the hallmarks of reversible DHP binding to L-type Ca2+ channels (nanomolar dissociation constants, stereoselectivity and modulation by other chemical classes of Ca2+ antagonist drugs) were maintained in α1ADHP, we analysed the pharmacological properties of (+)-[3H]isradipine-labelled α1ADHP Ca2+ channels after heterologous expression. Binding of (+)-isradipine (Ki 7.4 nM) and the non-benzoxadiazole DHPs nifedipine (Ki 86 nM), (±)-nitrendipine (Ki 33 nM) and (±)-nimodipine (Ki 67 nM) to α1ADHP occurred at low nanomolar Ki values. DHP binding was highly stereoselective [25-fold higher affinity for (+)-isradipine]. As with native channels it was stimulated by (+)-cis-diltiazem, (+)-tetrandrine and mibefradil. This suggested that the three-dimensional architecture of the channel pore was maintained within the non-L-type α1A subunit. To predict the three-dimensional arrangement of the DHP-binding residues we exploited the X-ray structure of a recently crystallized bacterial K+ channel (KcsA) as a template. Our model is based on the assumption that the Ca2+ channel S5 and S6 segments closely resemble the KcsA transmembrane folding architecture. In the absence of three-dimensional structural data for the α1 subunit this is currently the most reasonable approach for modelling this drug-interaction domain. Our model predicts that the previously identified DHP-binding residues form a binding pocket large enough to co-ordinate a single DHP molecule. It also implies that the four homologous Ca2+ channel repeats are arranged in a clockwise manner.

scholarly journals Cysteine Mutagenesis and Computer Modeling of the S6 Region of an Intermediate Conductance IKCa Channel

2002 ◽  
Vol 120 (1) ◽  
pp. 99-116 ◽  
Author(s):  
Manuel Simoes ◽  
Line Garneau ◽  
Hélène Klein ◽  
Umberto Banderali ◽  
Fadi Hobeila ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Structural Data ◽  
Structural Features ◽  
K Channel ◽  
Crystallographic Structure ◽  
Channel Pore ◽  
State Dependent ◽  
Cysteine Scanning Mutagenesis ◽  
Three Dimensional Models ◽  
State Configuration

Cysteine-scanning mutagenesis (SCAM) and computer-based modeling were used to investigate key structural features of the S6 transmembrane segment of the calcium-activated K+ channel of intermediate conductance IKCa. Our SCAM results show that the interaction of [2-(trimethylammonium)ethyl] methanethiosulfonate bromide (MTSET) with cysteines engineered at positions 275, 278, and 282 leads to current inhibition. This effect was state dependent as MTSET appeared less effective at inhibiting IKCa in the closed (zero Ca2+ conditions) than open state configuration. Our results also indicate that the last four residues in S6, from A283 to A286, are entirely exposed to water in open IKCa channels, whereas MTSET can still reach the 283C and 286C residues with IKCa maintained in a closed state configuration. Notably, the internal application of MTSET or sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) caused a strong Ca2+-dependent stimulation of the A283C, V285C, and A286C currents. However, in contrast to the wild-type IKCa, the MTSET-stimulated A283C and A286C currents appeared to be TEA insensitive, indicating that the MTSET binding at positions 283 and 286 impaired the access of TEA to the channel pore. Three-dimensional structural data were next generated through homology modeling using the KcsA structure as template. In accordance with the SCAM results, the three-dimensional models predict that the V275, T278, and V282 residues should be lining the channel pore. However, the pore dimensions derived for the A283–A286 region cannot account for the MTSET effect on the closed A283C and A286 mutants. Our results suggest that the S6 domain extending from V275 to V282 possesses features corresponding to the inner cavity region of KcsA, and that the COOH terminus end of S6, from A283 to A286, is more flexible than predicted on the basis of the closed KcsA crystallographic structure alone. According to this model, closure by the gate should occur at a point located between the T278 and V282 residues.

scholarly journals Three-Dimensional Structures of Carbohydrates and Where to Find Them

2020 ◽  
Vol 21 (20) ◽  
pp. 7702 ◽  
Author(s):  
Sofya I. Scherbinina ◽  
Philip V. Toukach
Keyword(s):  
Experimental Data ◽  
Molecular Modeling ◽  
Computational Methods ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Structural Data ◽  
Structural Features ◽  
Data Validation ◽  
Data Generation ◽  
Efficient Treatment

Analysis and systematization of accumulated data on carbohydrate structural diversity is a subject of great interest for structural glycobiology. Despite being a challenging task, development of computational methods for efficient treatment and management of spatial (3D) structural features of carbohydrates breaks new ground in modern glycoscience. This review is dedicated to approaches of chemo- and glyco-informatics towards 3D structural data generation, deposition and processing in regard to carbohydrates and their derivatives. Databases, molecular modeling and experimental data validation services, and structure visualization facilities developed for last five years are reviewed.

scholarly journals Structure of the Lectin Mannose 6-Phosphate Receptor Homology (MRH) Domain of Glucosidase II, an Enzyme That Regulates Glycoprotein Folding Quality Control in the Endoplasmic Reticulum

2013 ◽  
Vol 288 (23) ◽  
pp. 16460-16475 ◽  
Author(s):  
Linda J. Olson ◽  
Ramiro Orsi ◽  
Solana G. Alculumbre ◽  
Francis C. Peterson ◽  
Ivan D. Stigliano ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Dimensional Structure ◽  
Mannose Residue ◽  
Glucosidase Ii ◽  
Mannose 6 Phosphate ◽  
First Time ◽  
Conserved Residue

Here we report for the first time the three-dimensional structure of a mannose 6-phosphate receptor homology (MRH) domain present in a protein with enzymatic activity, glucosidase II (GII). GII is involved in glycoprotein folding in the endoplasmic reticulum. GII removes the two innermost glucose residues from the Glc3Man9GlcNAc2 transferred to nascent proteins and the glucose added by UDP-Glc:glycoprotein glucosyltransferase. GII is composed of a catalytic GIIα subunit and a regulatory GIIβ subunit. GIIβ participates in the endoplasmic reticulum localization of GIIα and mediates in vivo enhancement of N-glycan trimming by GII through its C-terminal MRH domain. We determined the structure of a functional GIIβ MRH domain by NMR spectroscopy. It adopts a β-barrel fold similar to that of other MRH domains, but its binding pocket is the most shallow known to date as it accommodates a single mannose residue. In addition, we identified a conserved residue outside the binding pocket (Trp-409) present in GIIβ but not in other MRHs that influences GII glucose trimming activity.

scholarly journals WONKAandOOMMPPAA: analysis of protein–ligand interaction data to direct structure-based drug design

2017 ◽  
Vol 73 (3) ◽  
pp. 279-285
Author(s):  
Charlotte M. Deane ◽  
Ian D. Wall ◽  
Darren V. S. Green ◽  
Brian D. Marsden ◽  
Anthony R. Bradley
Keyword(s):  
Three Dimensional ◽  
Structural Data ◽  
Data Sets ◽  
Interaction Data ◽  
Activity Data ◽  
Ligand Interaction ◽  
Structure Based Drug Design ◽  
Web Based ◽  
Protein Ligand Interaction ◽  
Ligand Activity

In this work, two freely available web-based interactive computational tools that facilitate the analysis and interpretation of protein–ligand interaction data are described. Firstly,WONKA, which assists in uncovering interesting and unusual features (for example residue motions) within ensembles of protein–ligand structures and enables the facile sharing of observations between scientists. Secondly,OOMMPPAA, which incorporates protein–ligand activity data with protein–ligand structural data using three-dimensional matched molecular pairs.OOMMPPAAhighlights nuanced structure–activity relationships (SAR) and summarizes available protein–ligand activity data in the protein context. In this paper, the background that led to the development of both tools is described. Their implementation is outlined and their utility using in-house Structural Genomics Consortium (SGC) data sets and openly available data from the PDB and ChEMBL is described. Both tools are freely available to use and download at http://wonka.sgc.ox.ac.uk/WONKA/ and http://oommppaa.sgc.ox.ac.uk/OOMMPPAA/.

scholarly journals THE APPLICABILITY OF THE CRYSTAL STRUCTURE OF TERMOTOGA MARITIMA 4--GLUCANOTRANSFERASE AS THE TEMPLATE FOR SULOCHRIN AS -GLUCOSIDASE INHIBITORS

2010 ◽  
Vol 9 (3) ◽  
pp. 479-486
Author(s):  
Rizna Triana Dewi ◽  
Yulia Anita ◽  
Enade Perdana Istyastono ◽  
Akhmad Darmawan ◽  
Muhamad Hanafi
Keyword(s):  
Crystal Structure ◽  
Saccharomyces Cerevisiae ◽  
Thermotoga Maritima ◽  
Binding Pocket ◽  
Operating Environment ◽  
High Sequence Identity ◽  
Glucosidase Inhibitor ◽  
Glucosidase Inhibitors ◽  
Docking Method ◽  
Binding Residues

Interaction of sulochrin to active site of glucosidase enzyme of Termotoga maritime has been studied by employing docking method using Molecular Operating Environment (MOE), in comparison with those are reports of established inhibitor α-glucosidase such as acarbose, miglitol and voglibose, and salicinol, as reference compounds. The crystal structure T. maritima α-glucanotransferase (PDB code: 1LWJ) can be employed to serve as the template in the virtual screening of S. cerevisiae α-glucosidase. The comparison between the binding pocket residues of Thermotoga maritima α-glucanotransferase and Saccharomyces cerevisiae α-glucosidase show a high sequence identity and similarity. The result showed that sulochrin could be located in the binding pocket and formed some interactions with the binding residues. The ligands showed proper predicted binding energy (-6.74 - -4.13 kcal/mol) and predicted Ki values (0.011 - 0.939 mM). Sulochrin has a possibility to serve as a lead compound in the development of new α-glucosidase inhibitor.   Keywords: Docking, sulochrin, α-glucosidase Inhibitor, Thermotoga maritime α-glucotransferase, Saccharomyces cerevisiae α-glucosidase, MOE

scholarly journals De Novo Molecule Design Through Molecular Generative Model Conditioned by 3D Information of Protein Binding Sites

2020 ◽  
Author(s):  
Mingyuan Xu ◽  
Ting Ran ◽  
Hongming Chen
Keyword(s):  
Protein Binding ◽  
De Novo ◽  
Structural Information ◽  
Chemical Space ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Generative Model ◽  
Coarse Grained ◽  
Molecule Design ◽  
3D Information

<p><i>De novo</i> molecule design through molecular generative model is gaining increasing attention in recent years. Here a novel generative model was proposed by integrating the 3D structural information of the protein binding pocket into the conditional RNN (cRNN) model to control the generation of drug-like molecules. In this model, the composition of protein binding pocket is effectively characterized through a coarse-grain strategy and the three-dimensional information of the pocket can be represented by the sorted eigenvalues of the coulomb matrix (EGCM) of the coarse-grained atoms composing the binding pocket. In current work, we used our EGCM method and a previously reported binding pocket descriptor DeeplyTough to train cRNN models and compared their performance. It has been shown that the molecules generated with the control of protein environment information have a clear tendency on generating compounds with higher similarity to the original X-ray bound ligand than normal RNN model and also achieving better performance in terms of docking scores. Our results demonstrate the potential application of EGCM controlled generative model for the targeted molecule generation and guided exploration on the drug-like chemical space. </p><p> </p>

A current assessment of photosystem II structure

1996 ◽  
Vol 16 (2) ◽  
pp. 159-187 ◽  
Author(s):  
William V. Nicholson ◽  
Robert C. Ford ◽  
Andreas Holzenburg
Keyword(s):  
Photosystem Ii ◽  
Structural Information ◽  
Three Dimensional ◽  
Structural Data ◽  
X Ray Diffraction ◽  
Membrane Protein Complex ◽  
Fast Absorption ◽  
Current Assessment ◽  
Electron Microscopical ◽  
A Current

This review covers the recent progress in the elucidation of the structure of photosystem II (PSII). Because much of the structural information for this membrane protein complex has been revealed by electron microscopy (EM), the review will also consider the specific technical and interpretation problems that arise with EM where they are of particular relevance to the structural data. Most recent reviews of photosystem II structure have concentrated on molecular studies of the PSII genes and on the likely roles of the subunits that they encode or they were mainly concerned with the biophysical data and fast absorption spectroscopy largely relating to electron transfer in various purified PSII preparations. In this review, we will focus on the approaches to the three-dimensional architecture of the complex and the lipid bilayer in which it is located (the thylakoid membrane) with special emphasis placed upon electron microscopical studies of PSII-containing thylakoid membranes. There are a few reports of 3D crystals of PSII and of associated X-ray diffraction measurements and although little structural information has so far been obtained from such studies (because of the lack of 3D crystals of sufficient quality), the prospects for such studies are also assessed.

scholarly journals The World of Cyclic Dinucleotides in Bacterial Behavior

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2462 ◽  
Author(s):  
Aline Dias da Purificação ◽  
Nathalia Marins de Azevedo ◽  
Gabriel Guarany de Araujo ◽  
Robson Francisco de Souza ◽  
Cristiane Rodrigues Guzzo
Keyword(s):  
Intracellular Signaling ◽  
Three Dimensional ◽  
Structural Data ◽  
Research Topic ◽  
Signaling Networks ◽  
Bacterial Cells ◽  
Signaling Systems ◽  
The World ◽  
Second Messenger Systems ◽  
Cyclic Dinucleotides

The regulation of multiple bacterial phenotypes was found to depend on different cyclic dinucleotides (CDNs) that constitute intracellular signaling second messenger systems. Most notably, c-di-GMP, along with proteins related to its synthesis, sensing, and degradation, was identified as playing a central role in the switching from biofilm to planktonic modes of growth. Recently, this research topic has been under expansion, with the discoveries of new CDNs, novel classes of CDN receptors, and the numerous functions regulated by these molecules. In this review, we comprehensively describe the three main bacterial enzymes involved in the synthesis of c-di-GMP, c-di-AMP, and cGAMP focusing on description of their three-dimensional structures and their structural similarities with other protein families, as well as the essential residues for catalysis. The diversity of CDN receptors is described in detail along with the residues important for the interaction with the ligand. Interestingly, genomic data strongly suggest that there is a tendency for bacterial cells to use both c-di-AMP and c-di-GMP signaling networks simultaneously, raising the question of whether there is crosstalk between different signaling systems. In summary, the large amount of sequence and structural data available allows a broad view of the complexity and the importance of these CDNs in the regulation of different bacterial behaviors. Nevertheless, how cells coordinate the different CDN signaling networks to ensure adaptation to changing environmental conditions is still open for much further exploration.

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