scholarly journals Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets

Structure ◽  
2016 ◽  
Vol 24 (5) ◽  
pp. 774-781 ◽  
Author(s):  
Glenn S. Van Aller ◽  
Alan P. Graves ◽  
Patricia A. Elkins ◽  
William G. Bonnette ◽  
Patrick J. McDevitt ◽  
...  
Keyword(s):  
Binding Pockets

Evolutionary Patterns of Retinal-Binding Pockets of Type I Rhodopsins and Their Functions†

2006 ◽  
Vol 82 (6) ◽  
pp. 1426 ◽  
Author(s):  
Larisa Adamian ◽  
Zheng Ouyang ◽  
Yan Yuan Tseng ◽  
Jie Liang
Keyword(s):  
Type I ◽  
Evolutionary Patterns ◽  
Binding Pockets

scholarly journals Creating enzymes and self-sufficient cells for biosynthesis of the non-natural cofactor nicotinamide cytosine dinucleotide

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xueying Wang ◽  
Yanbin Feng ◽  
Xiaojia Guo ◽  
Qian Wang ◽  
Siyang Ning ◽  
...  
Keyword(s):  
Biological Sciences ◽  
Escherichia Coli ◽  
Nicotinamide Adenine Dinucleotide ◽  
Chemical Biology ◽  
Reduced Form ◽  
Redox Transformations ◽  
Nicotinamide Mononucleotide ◽  
Self Sufficiency ◽  
Binding Pockets ◽  
Pathway Regulation

AbstractNicotinamide adenine dinucleotide (NAD) and its reduced form are indispensable cofactors in life. Diverse NAD mimics have been developed for applications in chemical and biological sciences. Nicotinamide cytosine dinucleotide (NCD) has emerged as a non-natural cofactor to mediate redox transformations, while cells are fed with chemically synthesized NCD. Here, we create NCD synthetase (NcdS) by reprograming the substrate binding pockets of nicotinic acid mononucleotide (NaMN) adenylyltransferase to favor cytidine triphosphate and nicotinamide mononucleotide over their regular substrates ATP and NaMN, respectively. Overexpression of NcdS alone in the model host Escherichia coli facilitated intracellular production of NCD, and higher NCD levels up to 5.0 mM were achieved upon further pathway regulation. Finally, the non-natural cofactor self-sufficiency was confirmed by mediating an NCD-linked metabolic circuit to convert L-malate into D-lactate. NcdS together with NCD-linked enzymes offer unique tools and opportunities for intriguing studies in chemical biology and synthetic biology.

scholarly journals Cryptic-site binding mechanism of medium-sized Bcl-xL inhibiting compounds elucidated by McMD-based dynamic docking simulations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gert-Jan Bekker ◽  
Ikuo Fukuda ◽  
Junichi Higo ◽  
Yoshifumi Fukunishi ◽  
Narutoshi Kamiya
Keyword(s):  
Ligand Binding ◽  
Cancer Progression ◽  
Hydrophobic Interactions ◽  
Binding Mechanism ◽  
Docking Simulations ◽  
Large Conformational Change ◽  
Binding Pockets ◽  
Dynamic Docking ◽  
Site Binding ◽  
Apo State

AbstractWe have performed multicanonical molecular dynamics (McMD) based dynamic docking simulations to study and compare the binding mechanism between two medium-sized inhibitors (ABT-737 and WEHI-539) that bind to the cryptic site of Bcl-xL, by exhaustively sampling the conformational and configurational space. Cryptic sites are binding pockets that are transiently formed in the apo state or are induced upon ligand binding. Bcl-xL, a pro-survival protein involved in cancer progression, is known to have a cryptic site, whereby the shape of the pocket depends on which ligand is bound to it. Starting from the apo-structure, we have performed two independent McMD-based dynamic docking simulations for each ligand, and were able to obtain near-native complex structures in both cases. In addition, we have also studied their interactions along their respective binding pathways by using path sampling simulations, which showed that the ligands form stable binding configurations via predominantly hydrophobic interactions. Although the protein started from the apo state, both ligands modulated the pocket in different ways, shifting the conformational preference of the sub-pockets of Bcl-xL. We demonstrate that McMD-based dynamic docking is a powerful tool that can be effectively used to study binding mechanisms involving a cryptic site, where ligand binding requires a large conformational change in the protein to occur.

scholarly journals Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1037
Author(s):  
Rodrigo Ochoa ◽  
Amaya Ortega-Pajares ◽  
Florencia A. Castello ◽  
Federico Serral ◽  
Darío Fernández Do Porto ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Screening Method ◽  
Molecular Targets ◽  
Leishmania Species ◽  
Akt Pathway ◽  
Protein Protein Interaction ◽  
Starting Point ◽  
Binding Pockets ◽  
Protein Protein Interaction Networks

Leishmaniasis is a public health disease that requires the development of more effective treatments and the identification of novel molecular targets. Since blocking the PI3K/AKT pathway has been successfully studied as an effective anticancer strategy for decades, we examined whether the same approach would also be feasible in Leishmania due to their high amount and diverse set of annotated proteins. Here, we used a best reciprocal hits protocol to identify potential protein kinase homologues in an annotated human PI3K/AKT pathway. We calculated their ligandibility based on available bioactivity data of the reported homologues and modelled their 3D structures to estimate the druggability of their binding pockets. The models were used to run a virtual screening method with molecular docking. We found and studied five protein kinases in five different Leishmania species, which are AKT, CDK, AMPK, mTOR and GSK3 homologues from the studied pathways. The compounds found for different enzymes and species were analysed and suggested as starting point scaffolds for the design of inhibitors. We studied the kinases’ participation in protein–protein interaction networks, and the potential deleterious effects, if inhibited, were supported with the literature. In the case of Leishmania GSK3, an inhibitor of its human counterpart, prioritized by our method, was validated in vitro to test its anti-Leishmania activity and indirectly infer the presence of the enzyme in the parasite. The analysis contributes to improving the knowledge about the presence of similar signalling pathways in Leishmania, as well as the discovery of compounds acting against any of these kinases as potential molecular targets in the parasite.

scholarly journals An UBR-box from a non-N-recognin: Crystal Structure of the UBR domain of UBR6

2014 ◽  
Vol 70 (a1) ◽  
pp. C306-C306
Author(s):  
Juliana Muñoz-Escobar ◽  
Guennadi Kozlov ◽  
Jean-François Trempe ◽  
Kalle Gehring
Keyword(s):  
Crystal Structure ◽  
Ubiquitin Proteasome System ◽  
Zinc Binding ◽  
Binding Motifs ◽  
Clear Explanation ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Binding Pockets ◽  
F Box Protein

The degradation of many short-lived proteins in eukaryotic cells is carried out by the Ubiquitin Proteasome System. The N-end rule pathway links the half-life of proteins to the identity of its N-terminal residue, also called N-degron. Destabilizing N-degrons, are recognized by E3 ubiquitin ligases termed N-recognins. N-degrons are grouped into type 1, composed of basic residues, and type 2, composed of bulky hydrophobic residues. In mammals, four N-recognins mediate the N-end rule pathway: UBR1, UBR2, UBR4 and UBR5. These proteins share a ~70-residue zinc finger-like motif termed the Ubiquitin Recognin (UBR) box, responsible for their specificity. The mammalian genome encodes at least three more UBR-box proteins: UBR3, UBR6/FBXO11 and UBR7. However, these UBRs cannot recognize any type of N-degrons. Our lab reported the crystal structures of the UBR boxes from the human UBR1 and UBR2, rationalizing the empirical rules for the classification of type 1 N-degrons. Despite the valuable information obtained from those structures there is not a clear explanation for the no recognition of N-degrons by other UBR-box proteins. Here we report the crystal structure of the UBR-box domain from UBR6 also known as FBXO11. UBR6 is a F-box protein of the SKP1-Cullin1-F-box (SCF) ubiquitin ligase complex and does not recognize any type of N-degrons. We crystallized a 77-residue fragment of the UBR-box of UBR6 and determined its structure at 1.7 Å resolution. Unexpectedly, this domain adopts an open conformation compared to UBR1-box, without any N-degron binding pockets. Its zinc-binding residues are conserved as in the N-recognins, but they are arranged in different zinc-binding motifs. Molecules form dimmers stabilized by zinc ions. The crystal had 4 molecules per asymmetric unit and space group P212121. For phasing we used Zn-SAD. With this structure we hope to obtain clues that explain the absence of N-degron recognition in some members of the UBR family.

Docking studies of Nickel-Peptide deformylase (PDF) inhibitors: Exploring the new binding pockets

2006 ◽  
Vol 122 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Qiang Wang ◽  
Datong Zhang ◽  
Jianwu Wang ◽  
Zhengting Cai ◽  
Weiren Xu
Keyword(s):  
Docking Studies ◽  
Peptide Deformylase ◽  
Binding Pockets

Ternary self-assemblies in water: forming a pentanuclear ReLn4 assembly by association of binuclear lanthanide binding pockets with fac-Re(CO)3(dinicotinate)2Cl

2013 ◽  
Vol 42 (46) ◽  
pp. 16255 ◽  
Author(s):  
Leila R. Hill ◽  
Octavia A. Blackburn ◽  
Michael W. Jones ◽  
Manuel Tropiano ◽  
Thomas Just Sørensen ◽  
...  
Keyword(s):  
Binding Pockets

scholarly journals Subunit stoichiometry and arrangement in a heteromeric glutamate-gated chloride channel

2016 ◽  
Vol 113 (5) ◽  
pp. E644-E653 ◽  
Author(s):  
Nurit Degani-Katzav ◽  
Revital Gortler ◽  
Lilach Gorodetzki ◽  
Yoav Paas
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Parasitic Diseases ◽  
Β Subunit ◽  
River Blindness ◽  
Subunit Stoichiometry ◽  
Binding Pockets ◽  
Extracellular Side ◽  
Electrophysiological Characterization

The invertebrate glutamate-gated chloride-selective receptors (GluClRs) are ion channels serving as targets for ivermectin (IVM), a broad-spectrum anthelmintic drug used to treat human parasitic diseases like river blindness and lymphatic filariasis. The native GluClR is a heteropentamer consisting of α and β subunit types, with yet unknown subunit stoichiometry and arrangement. Based on the recent crystal structure of a homomeric GluClαR, we introduced mutations at the intersubunit interfaces where Glu (the neurotransmitter) binds. By electrophysiological characterization of these mutants, we found heteromeric assemblies with two equivalent Glu-binding sites at β/α intersubunit interfaces, where the GluClβ and GluClα subunits, respectively, contribute the “principal” and “complementary” components of the putative Glu-binding pockets. We identified a mutation in the IVM-binding site (far away from the Glu-binding sites), which significantly increased the sensitivity of the heteromeric mutant receptor to both Glu and IVM, and improved the receptor subunits’ cooperativity. We further characterized this heteromeric GluClR mutant as a receptor having a third Glu-binding site at an α/α intersubunit interface. Altogether, our data unveil heteromeric GluClR assemblies having three α and two β subunits arranged in a counterclockwise β-α-β-α-α fashion, as viewed from the extracellular side, with either two or three Glu-binding site interfaces.

scholarly journals Binding-Site Identification and Genotypic Profiling of Hepatitis C Virus Polymerase Inhibitors

2007 ◽  
Vol 81 (13) ◽  
pp. 6909-6919 ◽  
Author(s):  
Frederik Pauwels ◽  
Wendy Mostmans ◽  
Ludo M. M. Quirynen ◽  
Liesbet van der Helm ◽  
Carlo W. Boutton ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Binding Site ◽  
Antiviral Drug ◽  
Variable Binding ◽  
Polymerase Inhibitors ◽  
Binding Site Identification ◽  
Virus Genotypes ◽  
Binding Pockets ◽  
Virus Mutant

ABSTRACT The search for hepatitis C virus polymerase inhibitors has resulted in the identification of several nonnucleoside binding pockets. The shape and nature of these binding sites differ across and even within diverse hepatitis C virus genotypes. These differences confront antiviral drug discovery with the challenge of finding compounds that are capable of inhibition in variable binding pockets. To address this, we have established a hepatitis C virus mutant and genotypic recombinant polymerase panel as a means of guiding medicinal chemistry through the elucidation of the site of action of novel inhibitors and profiling against genotypes. Using a genotype 1b backbone, we demonstrate that the recombinant P495L, M423T, M414T, and S282T mutant enzymes can be used to identify the binding site of an acyl pyrrolidine analog. We assess the inhibitory activity of this analog and other nonnucleoside inhibitors with our panel of enzyme isolates generated from clinical sera representing genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a.

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