scholarly journals Insights into the Importance of Hydrogen Bonding in the γ-Phosphate Binding Pocket of Myosin: Structural and Functional Studies of Serine 236,

Biochemistry ◽  
2010 ◽  
Vol 49 (23) ◽  
pp. 4897-4907 ◽  
Author(s):  
Jeremiah J. Frye ◽  
Vadim A. Klenchin ◽  
Clive R. Bagshaw ◽  
Ivan Rayment
Keyword(s):  
Hydrogen Bonding ◽  
Binding Pocket ◽  
Phosphate Binding ◽  
Functional Studies

NMR Spectroscopic Investigation of Mobility and Hydrogen Bonding of the Chromophore in the Binding Pocket of Phytochrome Proteins

ChemPhysChem ◽  
2010 ◽  
Vol 11 (6) ◽  
pp. 1248-1257 ◽  
Author(s):  
Marco Röben ◽  
Janina Hahn ◽  
Eva Klein ◽  
Tilman Lamparter ◽  
Georgios Psakis ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Spectroscopic Investigation ◽  
Binding Pocket

scholarly journals Improving the Substrate Affinity and Catalytic Efficiency of β-Glucosidase Bgl3A from Talaromyces leycettanus JCM12802 by Rational Design

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1882
Author(s):  
Wei Xia ◽  
Yingguo Bai ◽  
Pengjun Shi
Keyword(s):  
Hydrogen Bonding ◽  
Rational Design ◽  
Substrate Binding ◽  
Enzymatic Saccharification ◽  
Catalytic Efficiency ◽  
Binding Pocket ◽  
Glycoside Hydrolases ◽  
Cellulosic Biomass ◽  
Substrate Affinity ◽  
Hydrogen Bonding Networks

Improving the substrate affinity and catalytic efficiency of β-glucosidase is necessary for better performance in the enzymatic saccharification of cellulosic biomass because of its ability to prevent cellobiose inhibition on cellulases. Bgl3A from Talaromyces leycettanus JCM12802, identified in our previous work, was considered a suitable candidate enzyme for efficient cellulose saccharification with higher catalytic efficiency on the natural substrate cellobiose compared with other β-glucosidase but showed insufficient substrate affinity. In this work, hydrophobic stacking interaction and hydrogen-bonding networks in the active center of Bgl3A were analyzed and rationally designed to strengthen substrate binding. Three vital residues, Met36, Phe66, and Glu168, which were supposed to influence substrate binding by stabilizing adjacent binding site, were chosen for mutagenesis. The results indicated that strengthening the hydrophobic interaction between stacking aromatic residue and the substrate, and stabilizing the hydrogen-bonding networks in the binding pocket could contribute to the stabilized substrate combination. Four dominant mutants, M36E, M36N, F66Y, and E168Q with significantly lower Km values and 1.4–2.3-fold catalytic efficiencies, were obtained. These findings may provide a valuable reference for the design of other β-glucosidases and even glycoside hydrolases.

scholarly journals Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2322 ◽  
Author(s):  
Saw Simeon ◽  
Nuttapat Anuwongcharoen ◽  
Watshara Shoombuatong ◽  
Aijaz Ahmad Malik ◽  
Virapong Prachayasittikul ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Molecular Docking ◽  
Binding Pocket ◽  
Binding Energies ◽  
Acetylcholinesterase Inhibition ◽  
Qsar Modeling ◽  
Qsar Study ◽  
Data Set ◽  
Ache Inhibitors ◽  
Redundant Data

Alzheimer’s disease (AD) is a chronic neurodegenerative disease which leads to the gradual loss of neuronal cells. Several hypotheses for AD exists (e.g., cholinergic, amyloid, tau hypotheses, etc.). As per the cholinergic hypothesis, the deficiency of choline is responsible for AD; therefore, the inhibition of AChE is a lucrative therapeutic strategy for the treatment of AD. Acetylcholinesterase (AChE) is an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine that is essential for cognition and memory. A large non-redundant data set of 2,570 compounds with reported IC50values against AChE was obtained from ChEMBL and employed in quantitative structure-activity relationship (QSAR) study so as to gain insights on their origin of bioactivity. AChE inhibitors were described by a set of 12 fingerprint descriptors and predictive models were constructed from 100 different data splits using random forest. Generated models affordedR2, ${Q}_{\mathrm{CV }}^{2}$ and ${Q}_{\mathrm{Ext}}^{2}$ values in ranges of 0.66–0.93, 0.55–0.79 and 0.56–0.81 for the training set, 10-fold cross-validated set and external set, respectively. The best model built using the substructure count was selected according to the OECD guidelines and it affordedR2, ${Q}_{\mathrm{CV }}^{2}$ and ${Q}_{\mathrm{Ext}}^{2}$ values of 0.92 ± 0.01, 0.78 ± 0.06 and 0.78 ± 0.05, respectively. Furthermore, Y-scrambling was applied to evaluate the possibility of chance correlation of the predictive model. Subsequently, a thorough analysis of the substructure fingerprint count was conducted to provide informative insights on the inhibitory activity of AChE inhibitors. Moreover, Kennard–Stone sampling of the actives were applied to select 30 diverse compounds for further molecular docking studies in order to gain structural insights on the origin of AChE inhibition. Site-moiety mapping of compounds from the diversity set revealed three binding anchors encompassing both hydrogen bonding and van der Waals interaction. Molecular docking revealed that compounds13,5and28exhibited the lowest binding energies of −12.2, −12.0 and −12.0 kcal/mol, respectively, against human AChE, which is modulated by hydrogen bonding,π–πstacking and hydrophobic interaction inside the binding pocket. These information may be used as guidelines for the design of novel and robust AChE inhibitors.

scholarly journals Crystal Structures of Two Coronavirus ADP-Ribose-1″-Monophosphatases and Their Complexes with ADP-Ribose: a Systematic Structural Analysis of the Viral ADRP Domain

2008 ◽  
Vol 83 (2) ◽  
pp. 1083-1092 ◽  
Author(s):  
Yuanyuan Xu ◽  
Le Cong ◽  
Cheng Chen ◽  
Lei Wei ◽  
Qi Zhao ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Crystal Structures ◽  
Structural Information ◽  
Large Family ◽  
Binding Pocket ◽  
Structural Basis ◽  
Active Site Residues ◽  
Replication Process ◽  
Functional Studies ◽  
Group I

ABSTRACT The coronaviruses are a large family of plus-strand RNA viruses that cause a wide variety of diseases both in humans and in other organisms. The coronaviruses are composed of three main lineages and have a complex organization of nonstructural proteins (nsp's). In the coronavirus, nsp3 resides a domain with the macroH2A-like fold and ADP-ribose-1"-monophosphatase (ADRP) activity, which is proposed to play a regulatory role in the replication process. However, the significance of this domain for the coronaviruses is still poorly understood due to the lack of structural information from different lineages. We have determined the crystal structures of two viral ADRP domains, from the group I human coronavirus 229E and the group III avian infectious bronchitis virus, as well as their respective complexes with ADP-ribose. The structures were individually solved to elucidate the structural similarities and differences of the ADRP domains among various coronavirus species. The active-site residues responsible for mediating ADRP activity were found to be highly conserved in terms of both sequence alignment and structural superposition, whereas the substrate binding pocket exhibited variations in structure but not in sequence. Together with data from a previous analysis of the ADRP domain from the group II severe acute respiratory syndrome coronavirus and from other related functional studies of ADRP domains, a systematic structural analysis of the coronavirus ADRP domains was realized for the first time to provide a structural basis for the function of this domain in the coronavirus replication process.

scholarly journals OR24-01 Mutational Study of the GPR119 Receptor Binding Site

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Matthew D Rosales ◽  
Frank Dean ◽  
Evangelia Kotsikorou
Keyword(s):  
Hydrogen Bonding ◽  
Binding Site ◽  
Specific Activity ◽  
Md Simulations ◽  
Binding Pocket ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Receptor Model ◽  
Wild Type

Abstract The GPR119 receptor, a class A G-protein coupled receptor located in the pancreatic β cells, induces insulin production when activated. Due to its specific activity, the pharmaceutical industry has identified GPR119 as a target for the treatment for type 2 diabetes. The lack of a GRP119 crystal structure has hindered the study of the receptor so our laboratory developed GPR119 active and inactive homology models. Docking studies with the inactive receptor model indicated that two leucine residues facing the binding pocket, L5.43(169) and L6.52(242), may be involved in ligand activation. Additionally, a serine at the extracellular end of the pocket, S1.32(4), may help orient of the ligand in the binding pocket via hydrogen bonding. To gain further insight into the role of these residues and the receptor activation mechanism, molecular dynamics (MD) simulations and in vitro cAMP assays of the wild type and mutant receptors were employed. The software NAMD employing the CHARMM force field was used to carry out MD simulations of the active receptor model bound with the agonist AR231453 embedded in a hydrated lipid bilayer. Preliminary results indicate that L6.52(242), located on transmembrane helix (TMH) 6, does not face directly into the binding site and does not interact with the ligand, while L5.43(169), located on TMH5, does face into the binding site, potentially interacting directly with the ligand. Also, S1.32(4), because of its extracellular location, is solvated instead of interacting with the ligand. The in vitro studies overall support the MD simulations. The mutations L6.52(242)M and L6.52(242)A appear to have minimal to no effect on agonist-induced cAMP production, compared to the wild type. In contrast, the L5.43(169)M and L5.43(169)A mutations decrease the potency of activation by AR231453, indicating that L5.43(169) changes the shape of the binding pocket, affecting ligand binding and activation. Finally, the cAMP assays show that the S1.32(4)A mutant also shows decreased activity compared to the wild type, implying that the ligand may be losing a hydrogen bonding interaction when S1.32(4) is mutated to alanine.

scholarly journals A novel Hv1 inhibitor reveals a new mechanism of inhibition of a voltage-sensing domain

2021 ◽  
Vol 153 (9) ◽  
Author(s):  
Chang Zhao ◽  
Liang Hong ◽  
Saleh Riahi ◽  
Victoria T. Lim ◽  
Douglas J. Tobias ◽  
...  
Keyword(s):  
Md Simulations ◽  
Binding Pocket ◽  
Proton Channel ◽  
Voltage Sensing ◽  
Voltage Gated ◽  
Functional Studies ◽  
Mechanism Of Inhibition ◽  
Target Binding ◽  
Voltage Gated Ion Channels ◽  
Pore Domain

Voltage-gated sodium, potassium, and calcium channels consist of four voltage-sensing domains (VSDs) that surround a central pore domain and transition from a down state to an up state in response to membrane depolarization. While many types of drugs bind pore domains, the number of organic molecules known to bind VSDs is limited. The Hv1 voltage-gated proton channel is made of two VSDs and does not contain a pore domain, providing a simplified model for studying how small ligands interact with VSDs. Here, we describe a ligand, named HIF, that interacts with the Hv1 VSD in the up and down states. We find that HIF rapidly inhibits proton conduction in the up state by blocking the open channel, as previously described for 2-guanidinobenzimidazole and its derivatives. HIF, however, interacts with a site slowly accessible in the down state. Functional studies and MD simulations suggest that this interaction traps the compound in a narrow pocket lined with charged residues within the VSD intracellular vestibule, which results in slow recovery from inhibition. Our findings point to a “wrench in gears” mechanism whereby side chains within the binding pocket trap the compound as the teeth of interlocking gears. We propose that the use of screening strategies designed to target binding sites with slow accessibility, similar to the one identified here, could lead to the discovery of new ligands capable of interacting with VSDs of other voltage-gated ion channels in the down state.

scholarly journals Pairing interactions between nucleobases and ligands in aptamer:ligand complexes of riboswitches: Crystal structure analysis, classification, optimal structures and accurate interaction energies

2019 ◽  
Author(s):  
Preethi S. Prabhakar ◽  
Purshotam Sharma ◽  
Abhijit Mitra
Keyword(s):  
Hydrogen Bonding ◽  
Visual Inspection ◽  
Weak Interactions ◽  
Binding Pocket ◽  
Crystal Structure Analysis ◽  
Thiamine Pyrophosphate ◽  
Interaction Energies ◽  
Binding Pockets ◽  
Pairing Interactions

ABSTRACTIn the present work, sixty-seven crystal structures of the aptamer domains of RNA riboswitches, are chosen for analysis of the structure and strength of hydrogen bonding (pairing) interactions between nucleobases constituting the aptamer binding pockets and the bound ligands. A total of eighty unique base:ligand hydrogen-bonded pairs containing at least two hydrogen bonds were identified through visual inspection. Classification of these contacts in terms of the interacting edge of the aptamer nucleobase revealed that interactions involving the Watson-Crick edge are the most common, followed by the sugar edge of purines and the Hoogsteen edge of uracil. Alternatively, classification in terms of the chemical constitution of the ligand yields five unique classes of base:ligand pairs: base:base, base:amino acid, base:sugar, base:phosphate and base:other. Further, quantum mechanical (QM) geometry optimizations revealed that sixty seven out of eighty pairs exhibit stable geometries and optimal deviations from their macromolecular crystal occurrences. This indicates that these contacts are well-defined RNA aptamer:ligand interaction motifs. QM calculated interaction energies of base:ligand pairs reveal rich hydrogen bonding landscape, ranging from weak interactions (base:other, –3 kcal/mol) to strong (base:phosphate, –48 kcal/mol) contacts. The analysis was further extended to study the biological importance of base:ligand interactions in the binding pocket of the tetrahydrofolate riboswitch and thiamine pyrophosphate riboswitch. Overall, our study helps in understanding the structural and energetic features of base:ligand pairs in riboswitches, which could aid in developing meaningful hypotheses in context of RNA:ligand recognition. This can, in turn contribute towards current efforts to develop antimicrobials that target RNAs.

scholarly journals Structural Basis for PPARs Activation by the Dual PPARα/γ Agonist Sanguinarine: A Unique Mode of Ligand Recognition

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6012
Author(s):  
Siyu Tian ◽  
Rui Wang ◽  
Shuming Chen ◽  
Jialing He ◽  
Weili Zheng ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Target Genes ◽  
Binding Pocket ◽  
Binding Mode ◽  
Structural Basis ◽  
Peroxisome Proliferator ◽  
Functional Studies ◽  
Glucose And Lipid Metabolism ◽  
Peroxisome Proliferator Activated Receptors ◽  
Dual Agonist

Peroxisome proliferator-activated receptors (PPARs) play crucial roles in glucose and lipid metabolism and inflammation. Sanguinarine is a natural product that is isolated from Sanguinaria Canadensis, a potential therapeutic agent for intervention in chronic diseases. In this study, biochemical and cell-based promoter-reporter gene assays revealed that sanguinarine activated both PPARα and PPARγ, and enhanced their transcriptional activity; thus, sanguinarine was identified as a dual agonist of PPARα/γ. Similar to fenofibrate, sanguinarine upregulates the expression of PPARα-target genes in hepatocytes. Sanguinarine also modulates the expression of key PPARγ-target genes and promotes adipocyte differentiation, but with a lower adipogenic activity compared with rosiglitazone. We report the crystal structure of sanguinarine bound to PPARα, which reveals a unique ligand-binding mode of sanguinarine, dissimilar to the classic Y-shaped binding pocket, which may represent a new pharmacophore that can be optimized for selectively targeting PPARα. Further structural and functional studies uncover the molecular basis for the selectivity of sanguinarine toward PPARα/γ among all three PPARs. In summary, our study identifies a PPARα/γ dual agonist with a unique ligand-binding mode, and provides a promising and viable novel template for the design of dual-targeting PPARs ligands.

3′-Azidothymidine in the active site ofEscherichia colithymidine phosphorylase: the peculiarity of the binding on the basis of X-ray study

2014 ◽  
Vol 70 (4) ◽  
pp. 1155-1165 ◽  
Author(s):  
Vladimir Timofeev ◽  
Yulia Abramchik ◽  
Nadezda Zhukhlistova ◽  
Tatiana Muravieva ◽  
Ilya Fateev ◽  
...  
Keyword(s):  
Active Site ◽  
Thymidine Phosphorylase ◽  
Binding Pocket ◽  
Chemotherapeutic Agents ◽  
Nucleoside Analogues ◽  
Dimensional Structure ◽  
Phosphate Binding ◽  
X Ray ◽  
E Coli ◽  
Replacement Method

The structural study of complexes of thymidine phosphorylase (TP) with nucleoside analogues which inhibit its activity is of special interest because many of these compounds are used as chemotherapeutic agents. Determination of kinetic parameters showed that 3′-azido-3′-deoxythymidine (3′-azidothymidine; AZT), which is widely used for the treatment of human immunodeficiency virus, is a reversible noncompetitive inhibitor ofEscherichia colithymidine phosphorylase (TP). The three-dimensional structure ofE. coliTP complexed with AZT was solved by the molecular-replacement method and was refined at 1.52 Å resolution. Crystals for X-ray study were grown in microgravity by the counter-diffusion technique from a solution of the protein in phosphate buffer with ammonium sulfate as a precipitant. The AZT molecule was located with full occupancy in the electron-density maps in the nucleoside-binding pocket of TP, whereas the phosphate-binding pocket of the enzyme was occupied by phosphate (or sulfate) ion. The structure of the active-site cavity and conformational changes of the enzyme upon AZT binding are described in detail. It is found that the position of AZT differs remarkably from the positions of the pyrimidine bases and nucleoside analogues in other known complexes of pyrimidine phosphorylases, but coincides well with the position of 2′-fluoro-3′-azido-2′,3′-dideoxyuridine (N3FddU) in the recently investigated complex ofE. coliTP with this ligand (Timofeevet al., 2013). The peculiarities of the arrangement of N3FddU and 3′-azidothymidine in the nucleoside binding pocket of TP and correlations between the arrangement and inhibitory properties of these compounds are discussed.

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