scholarly journals Hydrophobic Residues near the Bilin Chromophore-Binding Pocket Modulate Spectral Tuning of Insert-Cys Subfamily Cyanobacteriochromes

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Sung Mi Cho ◽  
Sae Chae Jeoung ◽  
Ji-Young Song ◽  
Ji-Joon Song ◽  
Youn-Il Park
Keyword(s):  
Binding Pocket ◽  
Spectral Tuning ◽  
Hydrophobic Residues

scholarly journals Cation and anion channelrhodopsins: Sequence motifs and taxonomic distribution

2021 ◽  
Author(s):  
Elena G. Govorunova ◽  
Oleg A. Sineshchekov ◽  
Hai Li ◽  
Yumei Wang ◽  
Leonid S. Brown ◽  
...  
Keyword(s):  
Ion Selectivity ◽  
Transmembrane Helix ◽  
Control Cell ◽  
Algal Species ◽  
Binding Pocket ◽  
Metagenomic Sequencing ◽  
Sequence Motifs ◽  
Spectral Tuning ◽  
Patch Clamp Recording ◽  
Ionic Selectivity

ABSTRACTCation and anion channelrhodopsins (CCRs and ACRs, respectively) primarily from two algal species, Chlamydomonas reinhardtii and Guillardia theta, have become widely used as optogenetic tools to control cell membrane potential with light. We mined algal and other protist polynucleotide sequencing projects and metagenomic samples to identify 75 channelrhodopsin homologs from three channelrhodopsin families, including one revealed in dinoflagellates in this study. We carried out electrophysiological analysis of 33 natural channelrhodopsin variants from different phylogenetic lineages and 10 metagenomic homologs in search of sequence determinants of ion selectivity, photocurrent desensitization, and spectral tuning in channelrhodopsins. Our results show that association of a reduced number of glutamates near the conductance path with anion selectivity depends on a wider protein context, because prasinophyte homologs with the identical glutamate pattern as in cryptophyte ACRs are cation-selective. Desensitization is also broadly context-dependent, as in one branch of stramenopile ACRs and their metagenomic homologs its extent roughly correlates with phylogenetic relationship of their sequences. Regarding spectral tuning, two prasinophyte CCRs exhibit red-shifted spectra to 585 nm, although their retinal-binding pockets do not match those of previously known similarly red-shifted channelrhodopsins. In cryptophyte ACRs we identified three specific residue positions in the retinal-binding pocket that define the wavelength of their spectral maxima. Lastly, we found that dinoflagellate rhodopsins with a TCP motif in the third transmembrane helix and a metagenomic homolog exhibit channel activity.IMPORTANCEChannelrhodopsins are widely used in neuroscience and cardiology as research tools and are considered as prospective therapeutics, but their natural diversity and mechanisms remain poorly characterized. Genomic and metagenomic sequencing projects are producing an ever-increasing wealth of data, whereas biophysical characterization of the encoded proteins lags behind. In this study we used manual and automated patch clamp recording of representative members of four channelrhodopsin families including a family that we report in this study in dinoflagellates. Our results contribute to a better understanding of molecular determinants of ionic selectivity, photocurrent desensitization, and spectral tuning in channelrhodopsins.

scholarly journals Additive and epistatic effects influence spectral tuning in molluscan retinochrome opsin

2021 ◽  
Author(s):  
G Dalton Smedley ◽  
Kyle E McElroy ◽  
Jeanne M Serb
Keyword(s):  
Amino Acid ◽  
Blue Shift ◽  
Binding Pocket ◽  
Acid Sites ◽  
Site Directed Mutagenesis ◽  
Spectral Tuning ◽  
Closely Related Species ◽  
Absorbance Peak ◽  
The Relationship

The relationship between genotype and phenotype is nontrivial due to often complex molecular pathways that make it difficult to unambiguously relate phenotypes to specific genotypes. Photopigments, an opsin apoprotein bound to a light-absorbing chromophore, present an opportunity to directly relate the amino acid sequence to an absorbance peak phenotype (λmax). We examined this relationship by conducting a series of site-directed mutagenesis experiments of retinochrome, a non-visual opsin, from two closely related species: the common bay scallop, Argopecten irradians, and the king scallop, Pecten maximus. Using protein folding models, we identified three amino acid sites of likely functional importance and expressed mutated retinochrome proteins in vitro. Our results show that the mutation of amino acids lining the opsin binding pocket are responsible for fine spectral tuning, or small changes in the λmax of these light sensitive proteins. Most mutations caused a blue shift regardless of the retinochrome background, with shifts ranging from a 12 nm blue shift to a 5 nm red shift from the wild-type λmax. These mutations do not show an additive effect, but rather suggests the presence of epistatic interactions. This work highlights the importance of binding pocket shape in the evolution of spectral tuning and builds on our ability to relate genotypic changes to phenotypes in an emerging model for opsin functional analysis.

scholarly journals Docking studies reveal zerumbone targets β-catenin of the Wnt-β-catenin pathway in breast cancer

2018 ◽  
Vol 83 (5) ◽  
pp. 575-591 ◽  
Author(s):  
Ayesha Fatima ◽  
Bustamam Abdul ◽  
Rasedee Abdullah ◽  
Roghayeh Karjiban ◽  
Vannajan Lee
Keyword(s):  
Breast Cancer ◽  
Binding Pocket ◽  
Docking Studies ◽  
Hydrophobic Residues ◽  
Docking Protocol ◽  
Charmm Force Field ◽  
Hydrophobic Nature ◽  
Transcription Factor 4 ◽  
Positively Charged

Breast cancer is the second most common cancer among women worldwide. The Wnt??-catenin pathway appears to be deregulated in most cancer cells including breast cancer. The role of zerumbone, the active sesquiterpene from Zingiber zerumbet Roscoe, on the Wnt??-catenin pathway is relatively unknown, especially detailed molecular studies have yet to be published. Using the Chemistry at HARvard Macromolecular Mechanics (CHARMm) force field-based docking protocol, CDOCKER, the molecular interactions between zerumbone and key proteins of the Wnt??-catenin pathway were evaluated in this study. The results suggest that zerumbone has a strong affinity for free ?-catenin in the cytoplasm, as well as the ?-catenin?transcription factor 4 complex in the nucleus. The overall hydrophobic nature of zerumbone allowed its interaction with other hydrophobic residues, such as Trp383, while its active ?,?-unsaturated carbonyl facilitated its interaction with positively charged residues, such as Lys345, Arg386 and Asn415 in the ?-catenin binding pocket. However, the Wnt protein and its frizzled receptor showed no attraction to zerumbone.

Origin of Spectral Tuning in Rhodopsin—It Is Not the Binding Pocket

2007 ◽  
Vol 46 (1-2) ◽  
pp. 269-271 ◽  
Author(s):  
Sivakumar Sekharan ◽  
Minoru Sugihara ◽  
Volker Buss
Keyword(s):  
Binding Pocket ◽  
Spectral Tuning

Roles of Surface Hydrophobic Residues in the Interfacial CatalysisofBovinePancreaticPhospholipaseA2

Biochemistry ◽  
1996 ◽  
Vol 35 (26) ◽  
pp. 8794-8794
Author(s):  
B.-I. Lee ◽  
E. T. Yoon ◽  
W. Cho
Keyword(s):  
Hydrophobic Residues

Characterization of Recombinant Human Coagulation Factor XFriuli

1996 ◽  
Vol 75 (02) ◽  
pp. 313-317 ◽  
Author(s):  
D J Kim ◽  
A Girolami ◽  
H L James
Keyword(s):  
Catalytic Domain ◽  
Coagulation Factor ◽  
Molecular Size ◽  
Binding Pocket ◽  
Site Directed Mutagenesis ◽  
Bleeding Tendency ◽  
Factor X ◽  
Amino Terminal ◽  
Normal Plasma ◽  
Plasma Factor

SummaryNaturally occurring plasma factor XFriuli (pFXFr) is marginally activated by both the extrinsic and intrinsic coagulation pathways and has impaired catalytic potential. These studies were initiated to obtain confirmation that this molecule is multi-functionally defective due to the substitution of Ser for Pro at position 343 in the catalytic domain. By the Nelson-Long site-directed mutagenesis procedure a construct of cDNA in pRc/CMV was derived for recombinant factor XFriuli (rFXFr) produced in human embryonic (293) kidney cells. The rFXFr was purified and shown to have a molecular size identical to that of normal plasma factor X (pFX) by gel electrophoretic, and amino-terminal sequencing revealed normal processing cleavages. Using recombinant normal plasma factor X (rFXN) as a reference, the post-translational y-carboxy-glutamic acid (Gla) and (β-hydroxy aspartic acid (β-OH-Asp) content of rFXFr was over 85% and close to 100%, respectively, of expected levels. The specific activities of rFXFr in activation and catalytic assays were the same as those of pFXFr. Molecular modeling suggested the involvement of a new H-bond between the side-chains of Ser-343 and Thr-318 as they occur in anti-parallel (3-pleated sheets near the substrate-binding pocket of pFXFr. These results support the conclusion that the observed mutation in pFXFr is responsible for its dysfunctional activation and catalytic potentials, and that it accounts for the moderate bleeding tendency in the homozygous individuals who possess this variant procoagulant.

Assemblies of D-peptides for Targeting Cell Nucleolus

2019 ◽  
Author(s):  
Huaimin Wang ◽  
Zhaoqianqi Feng ◽  
Weiyi Tan ◽  
Bing Xu
Keyword(s):  
Particle Morphology ◽  
Side Chain ◽  
Mechanism Study ◽  
Structural Analogue ◽  
Hydrophobic Residues ◽  
Subcellular Organelles ◽  
First Case ◽  
New Strategy ◽  
Peptide Derivative ◽  
Peptide Nanoparticles

<p>Selectively targeting cell nucleolus remains a challenge. Here we report the first case that D-peptides form membraneless molecular condensates with RNA for targeting cell nucleolus. A D-peptide derivative, enriched with lysine and hydrophobic residues, self-assembles to form nanoparticles, which enter cells through clathrin dependent endocytosis and mainly accumulate at cell nucleolus. Structural analogue of the D-peptide reveals that particle morphology of the assemblies, which depends on the side chain modification, favors the cellular uptake. Contrasting to those of the D-peptide, the assemblies of the corresponding L-enantiomer largely localize in cell lysosomes. Preliminary mechanism study suggests that the D-peptide nanoparticles interact with RNA to form membraneless condensates in the nucleolus, which further induces DNA damage and results in cell death. This work illustrates a new strategy for rationally designing supramolecular assemblies of D-peptides for targeting subcellular organelles.</p>

DESIGN OF NEW PEROXISOME PROLIFERATORS GAMMA ACTIVATED RECEPTOR AGONISTS (PPARγ) VIA QSAR BASED MODELING

2018 ◽  
pp. 23-26 ◽  
Author(s):  
Tripathi RB ◽  
Jain J ◽  
Siddiqui AW
Keyword(s):  
Molecular Descriptor ◽  
Binding Pocket ◽  
Peroxisome Proliferators ◽  
Qsar Study ◽  
Qsar Analysis ◽  
Qsar Models ◽  
Artery Disease ◽  
Peroxisome Proliferators Activated Receptors ◽  
Recent Attention

The Peroxisome proliferators-activated receptors (PPARs) are one of the nuclear fatty acid receptors, which contain a type II zincfinger DNA binding pattern and a hydrophobic ligand binding pocket. These receptors are thought to play an essential role in metabolic diseasessuch as obesity, insulin resistance, and coronary artery disease. Therefore Peroxisome Proliferators-Activated Receptor (PPARγ) activators havedrawn great recent attention in the clinical management of type 2 diabetes mellitus, prompting several attempts to discover and optimize newPPARγ activators. Objective: The aim of the study was to finding new selective human PPARγ (PPARγ) modulators that are able to improveglucose homeostasis with reduced side effects compared with TZDs and identify the specific molecular descriptor and structural constraint toimprove the agonist activity of PPARγ analogs. Material and Method: Software’s that was used for this study include S.P. Gupta QSARsoftware (QSAR analysis), Valstat (Comparative QSAR analysis and calculation of L-O-O, Q2, r2, Spress), BILIN (Comparative QSAR analysisand calculation of Q2, r, S, Spress, and F), etc., allowing directly performing statistical analysis. Then multiple linear regression based QSARsoftware (received from BITS-Pilani, India) generates QSAR equations. Result and Discussion: In this study, we explored the quantitativestructure–activity relationship (QSAR) study of a series of meta-substituted Phenyl-propanoic acids as Peroxisome Proliferators Gamma activatedreceptor agonists (PPARγ).The activities of meta-substituted Phenyl-propanoic acids derivatives correlated with various physicochemical, electronic and steric parameters.Conclusion: The identified QSAR models highlighted the significance of molar refractivity and hydrophobicity to the biological activity.

Structural Insights into Azole-based Inhibitors of Heme Oxygenase-1: Development of Selective Compounds for Therapeutic Applications

2019 ◽  
Vol 25 (42) ◽  
pp. 5803-5821 ◽  
Author(s):  
Mona N. Rahman ◽  
Dragic Vukomanovic ◽  
Jason Z. Vlahakis ◽  
Walter A. Szarek ◽  
Kanji Nakatsu ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Competitive Inhibition ◽  
Cytochromes P450 ◽  
Structural Similarity ◽  
Binding Pocket ◽  
Initial Study ◽  
Structural Basis ◽  
Heme Oxygenase 1 ◽  
Design Strategies ◽  
Inhibitor Binding

The development of isozyme-selective heme oxygenase (HO) inhibitors promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties with a role in several disease states; thus, it is an enticing therapeutic target. Historically, the metalloporphyrins have been used as competitive HO inhibitors based on their structural similarity to the substrate, heme. However, heme’s important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), results in non-selectivity being an unfortunate side effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort over a decade ago to develop novel compounds as potent, selective inhibitors of HO. The result was the creation of the first generation of non-porphyrin based, non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated and provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies. Notably, HO-1 inhibitors are of particular interest for the treatment of hyperbilirubinemia and certain types of cancer. Key features based on this initial study have already been used by others to discover additional potential HO-1 inhibitors. Moreover, studies have begun to use selected compounds and determine their effects in some disease models.

Sign in / Sign up

Export Citation Format

Share Document