Glycogen phosphorylase revisited: extending the resolution of the R- and T-state structures of the free enzyme and in complex with allosteric activators

2021 ◽  
Vol 77 (9) ◽  
pp. 303-311
Author(s):  
Demetres D. Leonidas ◽  
Spyros E. Zographos ◽  
Katerina E. Tsitsanou ◽  
Vassiliki T. Skamnaki ◽  
George Stravodimos ◽  
...  
Keyword(s):  
Drug Design ◽  
Binding Site ◽  
Crystal Structures ◽  
Glycogen Phosphorylase ◽  
Structural Features ◽  
Terminal Segment ◽  
Structure Based Drug Design ◽  
Allosteric Transition ◽  
Α Helix ◽  
T State

The crystal structures of free T-state and R-state glycogen phosphorylase (GP) and of R-state GP in complex with the allosteric activators IMP and AMP are reported at improved resolution. GP is a validated pharmaceutical target for the development of antihyperglycaemic agents, and the reported structures may have a significant impact on structure-based drug-design efforts. Comparisons with previously reported structures at lower resolution reveal the detailed conformation of important structural features in the allosteric transition of GP from the T-state to the R-state. The conformation of the N-terminal segment (residues 7–17), the position of which was not located in previous T-state structures, was revealed to form an α-helix (now termed α0). The conformation of this segment (which contains Ser14, phosphorylation of which leads to the activation of GP) is significantly different between the T-state and the R-state, pointing in opposite directions. In the T-state it is packed between helices α4 and α16 (residues 104–115 and 497–508, respectively), while in the R-state it is packed against helix α1 (residues 22′–38′) and towards the loop connecting helices α4′ and α5′ of the neighbouring subunit. The allosteric binding site where AMP and IMP bind is formed by the ordering of a loop (residues 313–326) which is disordered in the free structure, and adopts a conformation dictated mainly by the type of nucleotide that binds at this site.

scholarly journals Structural insights into targeting of the colchicine binding site by ELR510444 and parbendazole to achieve rational drug design

RSC Advances ◽  
2021 ◽  
Vol 11 (31) ◽  
pp. 18938-18944
Author(s):  
Jia-Hong Lei ◽  
Ling-Ling Ma ◽  
Jing-Hong Xian ◽  
Hai Chen ◽  
Jian-Jian Zhou ◽  
...  
Keyword(s):  
Drug Design ◽  
Binding Site ◽  
Crystal Structures ◽  
Rational Drug Design ◽  
Colchicine Binding Site ◽  
Rational Drug ◽  
Structural Insights

Crystal structures of tubulin complexed with ELR510444 and parbendazole facilitate the design of novel colchicine binding site inhibitors.

3D U-Net: A voxel-based method in binding site prediction of protein structure

2021 ◽  
Vol 19 (02) ◽  
pp. 2150006
Author(s):  
Fatemeh Nazem ◽  
Fahimeh Ghasemi ◽  
Afshin Fassihi ◽  
Alireza Mehri Dehnavi
Keyword(s):  
Drug Design ◽  
Binding Site ◽  
Binding Sites ◽  
Semantic Segmentation ◽  
Structure Based Drug Design ◽  
Site Prediction ◽  
Binding Site Prediction ◽  
Novel Proteins ◽  
Proposed Model ◽  
Deep Learning Model

Binding site prediction for new proteins is important in structure-based drug design. The identified binding sites may be helpful in the development of treatments for new viral outbreaks in the world when there is no information available about their pockets with COVID-19 being a case in point. Identification of the pockets using computational methods, as an alternative method, has recently attracted much interest. In this study, the binding site prediction is viewed as a semantic segmentation problem. An improved 3D version of the U-Net model based on the dice loss function is utilized to predict the binding sites accurately. The performance of the proposed model on the independent test datasets and SARS-COV-2 shows the segmentation model could predict the binding sites with a more accurate shape than the recently published deep learning model, i.e. DeepSite. Therefore, the model may help predict the binding sites of proteins and could be used in drug design for novel proteins.

scholarly journals Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939

2012 ◽  
Vol 68 (2) ◽  
pp. 115-118 ◽  
Author(s):  
Christina A. Kirby ◽  
Atwood Cheung ◽  
Aleem Fazal ◽  
Michael D. Shultz ◽  
Travis Stams
Keyword(s):  
Drug Design ◽  
Crystal Structures ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Donor Site ◽  
Structure Based Drug Design ◽  
Crystallization System ◽  
Tankyrase 1

The crystal structures of tankyrase 1 (TNKS1) in complex with two small-molecule inhibitors, PJ34 and XAV939, both at 2.0 Å resolution, are reported. The structure of TNKS1 in complex with PJ34 reveals two molecules of PJ34 bound in the NAD+donor pocket. One molecule is in the nicotinamide portion of the pocket, as previously observed in other PARP structures, while the second molecule is bound in the adenosine portion of the pocket. Additionally, unlike the unliganded crystallization system, the TNKS1–PJ34 crystallization system has the NAD+donor site accessible to bulk solvent in the crystal, which allows displacement soaking. The TNKS1–PJ34 crystallization system was used to determine the structure of TNKS1 in complex with XAV939. These structures provide a basis for the start of a structure-based drug-design campaign for TNKS1.

scholarly journals Crystal structures of human ENPP1 in apo and bound forms

2020 ◽  
Vol 76 (9) ◽  
pp. 889-898 ◽  
Author(s):  
Matthew L. Dennis ◽  
Janet Newman ◽  
Olan Dolezal ◽  
Meghan Hattarki ◽  
Regina N. Surjadi ◽  
...  
Keyword(s):  
Immune System ◽  
Drug Design ◽  
Crystal Structures ◽  
Cyclic Gmp ◽  
Therapeutic Target ◽  
Structure Based Drug Design ◽  
X Ray ◽  
Crystallization System ◽  
Causes Of Mortality ◽  
Cancerous Cells

Cancer is one of the leading causes of mortality in humans, and recent work has focused on the area of immuno-oncology, in which the immune system is used to specifically target cancerous cells. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an emerging therapeutic target in human cancers owing to its role in degrading cyclic GMP-AMP (cGAMP), an agonist of the stimulator of interferon genes (STING). The available structures of ENPP1 are of the mouse enzyme, and no structures are available with anything other than native nucleotides. Here, the first X-ray crystal structures of the human ENPP1 enzyme in an apo form, with bound nucleotides and with two known inhibitors are presented. The availability of these structures and a robust crystallization system will allow the development of structure-based drug-design campaigns against this attractive cancer therapeutic target.

scholarly journals High-resolution crystal structures of the D1 and D2 domains of protein tyrosine phosphatase epsilon for structure-based drug design

2018 ◽  
Vol 74 (10) ◽  
pp. 1015-1026 ◽  
Author(s):  
George T. Lountos ◽  
Sreejith Raran-Kurussi ◽  
Bryan M. Zhao ◽  
Beverly K. Dyas ◽  
Terrence R. Burke ◽  
...  
Keyword(s):  
Drug Design ◽  
Crystal Structures ◽  
Phosphatase Activity ◽  
Protein Tyrosine Phosphatase ◽  
High Throughput Screening ◽  
Catalytic Domain ◽  
Tyrosine Phosphatase ◽  
Triple Mutant ◽  
Structure Based Drug Design ◽  
Protein Tyrosine

Here, new crystal structures are presented of the isolated membrane-proximal D1 and distal D2 domains of protein tyrosine phosphatase epsilon (PTP∊), a protein tyrosine phosphatase that has been shown to play a positive role in the survival of human breast cancer cells. A triple mutant of the PTP∊ D2 domain (A455N/V457Y/E597D) was also constructed to reconstitute the residues of the PTP∊ D1 catalytic domain that are important for phosphatase activity, resulting in only a slight increase in the phosphatase activity compared with the native D2 protein. The structures reported here are of sufficient resolution for structure-based drug design, and a microarray-based assay for high-throughput screening to identify small-molecule inhibitors of the PTP∊ D1 domain is also described.

scholarly journals An enhanced-sampling MD-based protocol for molecular docking

2018 ◽  
Author(s):  
Andrea Basciu ◽  
Giuliano Malloci ◽  
Fabio Pietrucci ◽  
Alexandre M. J. J. Bonvin ◽  
Attilio V. Vargiu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Drug Design ◽  
Binding Site ◽  
Conformational Changes ◽  
Protein Complexes ◽  
Structural Diversity ◽  
Collective Variables ◽  
Structure Based Drug Design ◽  
Ensemble Docking

AbstractUnderstanding molecular recognition of proteins by small molecules is key for drug design. Despite the number of experimental structures of ligand-protein complexes keeps growing, the number of available targets remains limited compared to the druggable genome, and structural diversity is generally low, which affects the chemical variance of putative lead compounds. From a computational perspective, molecular docking is widely used to mimic ligand-protein association in silico. Ensemble-docking approaches include flexibility through a set of different conformations of the protein obtained either experimentally or from computer simulations, e.g. molecular dynamics. However, structures prone to host (the correct) ligands are generally poorly sampled by standard molecular dynamics simulations of the apo protein. In order to address this limitation, we introduce a computational approach based on metadynamics simulations (EDES - Ensemble-Docking with Enhanced-sampling of pocket Shape) to generate druggable conformations of proteins only exploiting their apo structures. This is achieved by defining a set of collective variables that effectively sample different shapes of the binding site, ultimately mimicking the steric effect due to ligands to generate holo-like binding site geometries. We assessed the method on two challenging proteins undergoing different extents of conformational changes upon ligand binding. In both cases our protocol generated a significant fraction of structures featuring a low RMSD from the experimental holo conformation. Moreover, ensemble docking calculations using those conformations yielded native-like poses among the top ranked ones for both targets. This proof of concept study paves the route towards an automated workflow to generate druggable conformations of proteins, which should become a precious tool for structure-based drug design.

scholarly journals Ligand docking and binding site analysis with pymol and autodock/vina

2015 ◽  
Vol 4 (2) ◽  
pp. 168 ◽  
Author(s):  
Mohd. Ahmar Rauf ◽  
Swaleha Zubair ◽  
Asim Azhar
Keyword(s):  
Molecular Docking ◽  
Drug Design ◽  
Three Dimensional ◽  
Structural Features ◽  
Docking Studies ◽  
Ligand Docking ◽  
Structure Based Drug Design ◽  
Site Analysis ◽  
User Friendly ◽  
Autodock 4.2

<p>Docking of various therapeutically important chemical entities to the specific target sites offers a meaningful strategy that may have tremendous scope in a drug design process. For a thorough understanding of the structural features that determine the strength of bonding between a ligand with its receptor, an insight to visualize binding geometries and interaction is mandatory. Bioinformatical as well as graphical software ‘PyMOL’ in combination with the molecular docking suites Autodock and Vina allows the study of molecular combination to visualize and understand the structure-based drug design efforts. In the present study, we outlined a user friendly method to perform molecular docking using vina and finally the results were analyzed in pymol in both two as well as three-dimensional orientation. The operation bypasses the steps that are involved in docking using cygwin terminal like formation of gpf and dpf files. The simple and straight-forward operation method does not require formal bioinformatics training to apprehend molecular docking studies using AutoDock 4.2 program.</p>

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