scholarly journals Inhibition of Mycobacterium-RmlA by Molecular Modeling, Dynamics Simulation, and Docking

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
N. Harathi ◽  
Madhusudana Pulaganti ◽  
C. M. Anuradha ◽  
Suresh Kumar Chitta
Keyword(s):  
Drug Targets ◽  
Rational Design ◽  
3D Structure ◽  
Reliability Assessment ◽  
Comparative Modeling ◽  
Structure And Function ◽  
Dynamics Simulation ◽  
Structural Refinement ◽  
And Function ◽  
Key Residues

The increasing resistance to anti-tb drugs has enforced strategies for finding new drug targets against Mycobacterium tuberculosis (Mtb). In recent years enzymes associated with the rhamnose pathway in Mtb have attracted attention as drug targets. The present work is on α-D-glucose-1-phosphate thymidylyltransferase (RmlA), the first enzyme involved in the biosynthesis of L-rhamnose, of Mtb cell wall. This study aims to derive a 3D structure of RmlA by using a comparative modeling approach. Structural refinement and energy minimization of the built model have been done with molecular dynamics. The reliability assessment of the built model was carried out with various protein checking tools such as Procheck, Whatif, ProsA, Errat, and Verify 3D. The obtained model investigates the relation between the structure and function. Molecular docking interactions of Mtb-RmlA with modified EMB (ethambutol) ligands and natural substrate have revealed specific key residues Arg13, Lys23, Asn109, and Thr223 which play an important role in ligand binding and selection. Compared to all EMB ligands, EMB-1 has shown better interaction with Mtb-RmlA model. The information thus discussed above will be useful for the rational design of safe and effective inhibitors specific to RmlA enzyme pertaining to the treatment of tuberculosis.

Structure prediction of SPAK C-terminal domain and analysis of its binding to RFXV/I motifs by homology modelling, docking, and molecular dynamics simulation studies

2020 ◽  
Vol 16 ◽  
Author(s):  
Mubarak A. Alamri ◽  
Ahmed D. Alafnan ◽  
Obaid Afzal ◽  
Alhumaidi B. Alabbas ◽  
Safar M. Alqahtani
Keyword(s):  
Molecular Dynamic ◽  
Dynamic Stability ◽  
Md Simulation ◽  
Homology Modelling ◽  
Antihypertensive Agents ◽  
Structure And Function ◽  
Dynamics Simulation ◽  
Dimensional Structure ◽  
Terminal Domain ◽  
And Function

Background: The STE20/SPS1-related proline/alanine-rich kinase (SPAK) is a component of WNKSPAK/OSR1 signaling pathway that plays an essential role in blood pressure regulation. The function of SPAK is mediated by its highly conserved C-terminal domain (CTD) that interacts with RFXV/I motifs of upstream activators, WNK kinases, and downstream substrate, cation-chloride cotransporters. Objective: To determine and validate the three-dimensional structure of the CTD of SPAK and to study and analyze its interaction with the RFXV/I motifs. Methods: A homology model of SPAK CTD was generated and validated through multiple approaches. The model was based on utilizing the OSR1 protein kinase as a template. This model was subjected to 100 ns molecular dynamic (MD) simulation to evaluate its dynamic stability. The final equilibrated model was used to dock the RFQV-peptide derived from WNK4 into the primary pocket that was determined based on the homology sequence between human SPAK and OSR1 CTDs. The mechanism of interaction, conformational rearrangement and dynamic stability of the binding of RFQV-peptide to SPAK CTD were characterized by molecular docking and molecular dynamic simulation. Results: The MD simulation suggested that the binding of RFQV induces a large conformational change due to the distribution of salt bridge within the loop regions. These results may help in understanding the relation between the structure and function of SPAK CTD and to support drug design of potential SPAK kinase inhibitors as antihypertensive agents. Conclusion: This study provides deep insight into SPAK CTD structure and function relationship.

scholarly journals Modeling and Molecular Dynamics of the 3D Structure of the HPV16 E7 Protein and Its Variants

2021 ◽  
Vol 22 (3) ◽  
pp. 1400
Author(s):  
Ciresthel Bello-Rios ◽  
Sarita Montaño ◽  
Olga Lilia Garibay-Cerdenares ◽  
Lilian Esmeralda Araujo-Arcos ◽  
Marco Antonio Leyva-Vázquez ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
3D Structure ◽  
Epidemiological Studies ◽  
Dynamics Simulation ◽  
Structural Refinement ◽  
Oncogenic Potential ◽  
Structural Differences ◽  
Reference Protein ◽  
E6 And E7 ◽  
First Time

The oncogenic potential of high-risk human papillomavirus (HPV) is predicated on the production of the E6 and E7 oncoproteins, which are responsible for disrupting the control of the cell cycle. Epidemiological studies have proposed that the presence of the N29S and H51N variants of the HPV16 E7 protein is significantly associated with cervical cancer. It has been suggested that changes in the amino acid sequence of E7 variants may affect the oncoprotein 3D structure; however, this remains uncertain. An analysis of the structural differences of the HPV16 E7 protein and its variants (N29S and H51N) was performed through homology modeling and structural refinement by molecular dynamics simulation. We propose, for the first time, a 3D structure of the E7 reference protein and two of Its variants (N29S and H51N), and conclude that the mutations induced by the variants in N29S and H51N have a significant influence on the 3D structure of the E7 protein of HPV16, which could be related to the oncogenic capacity of this protein.

scholarly journals Cytolethal Distending Toxin Subunit B: A Review of Structure–Function Relationship

Toxins ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 595 ◽  
Author(s):  
Benoît J. Pons ◽  
Julien Vignard ◽  
Gladys Mirey
Keyword(s):  
Pathogenic Bacteria ◽  
Molecular Mechanisms ◽  
3D Structure ◽  
Cytolethal Distending Toxin ◽  
Experimental Systems ◽  
Bacterial Virulence Factor ◽  
Function Relationship ◽  
And Function ◽  
Key Residues ◽  
Cell Cycle Block

The Cytolethal Distending Toxin (CDT) is a bacterial virulence factor produced by several Gram-negative pathogenic bacteria. These bacteria, found in distinct niches, cause diverse infectious diseases and produce CDTs differing in sequence and structure. CDTs have been involved in the pathogenicity of the associated bacteria by promoting persistent infection. At the host-cell level, CDTs cause cell distension, cell cycle block and DNA damage, eventually leading to cell death. All these effects are attributable to the catalytic CdtB subunit, but its exact mode of action is only beginning to be unraveled. Sequence and 3D structure analyses revealed similarities with better characterized proteins, such as nucleases or phosphatases, and it has been hypothesized that CdtB exerts a biochemical activity close to those enzymes. Here, we review the relationships that have been established between CdtB structure and function, particularly by mutation experiments on predicted key residues in different experimental systems. We discuss the relevance of these approaches and underline the importance of further study in the molecular mechanisms of CDT toxicity, particularly in the context of different pathological conditions.

scholarly journals Deciphering the 3D Structure and Function of Phosphofructokinase from Fission Yeast

2014 ◽  
Vol 20 (S3) ◽  
pp. 1246-1247
Author(s):  
Shaun Benjamin ◽  
Michael Radermacher ◽  
Teresa Ruiz
Keyword(s):  
Fission Yeast ◽  
3D Structure ◽  
Structure And Function ◽  
And Function

scholarly journals Targeting the bacterial SOS response for new antimicrobial agents: drug targets, molecular mechanisms and inhibitors

2021 ◽  
Author(s):  
Thomas Lanyon-Hogg
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Structure And Function ◽  
Drug Resistant ◽  
Target Validation ◽  
Sos Pathway ◽  
And Function

Antimicrobial resistance is a pressing threat to global health, with multidrug-resistant pathogens becoming increasingly prevalent. The bacterial SOS pathway functions in response to DNA damage that occurs during infection, initiating several pro-survival and resistance mechanisms, such as DNA repair and hypermutation. This makes SOS pathway components potential targets that may combat drug-resistant pathogens and decrease resistance emergence. This review discusses the mechanism of the SOS pathway; the structure and function of potential targets AddAB, RecBCD, RecA and LexA; and efforts to develop selective small-molecule inhibitors of these proteins. These inhibitors may serve as valuable tools for target validation and provide the foundations for desperately needed novel antibacterial therapeutics.

scholarly journals Cohesin Releasing Factor WAPL Regulates Genome Structure and Function of Mature T Cells

2021 ◽  
Author(s):  
Yaping Sun ◽  
Gabrielle A. Dotson ◽  
Lindsey A. Muir ◽  
Scott Ronquist ◽  
Katherine Oravecz-Wilson ◽  
...  
Keyword(s):  
T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Genome Structure ◽  
3D Structure ◽  
Three Dimensional ◽  
Structure And Function ◽  
Cell Functions ◽  
And Function

ABSTRACTThe cohesin complex modulates gene expression and cellular functions by shaping three-dimensional (3D) organization of chromatin. WAPL, cohesin’s DNA releasing factor, regulates 3D chromatin architecture. The 3D genome structure and its relevance to mature T cell functions is not well understood. We show that in vivo lymphopenic expansion, and allo-antigen driven proliferation, alters the 3D structure and function of the genome in mature T cells. Conditional deletion of Wapl in T cells reduced long-range genomic interactions, altered chromatin A/B compartments and the topologically associating domains (TAD) of the chromatin in T cells at baseline. Comparison of chromatin structure in normal and WAPL-deficient T cells after lymphopenic and allo-antigen driven stimulation revealed reduced loop extensions with changes in cell cycling genes. WAPL-mediated changes in 3D architecture of chromatin regulated activation, cycling and proliferation of T cells in vitro and in vivo. Finally, WAPL-deficient T cells caused reduced severity of graft-versus-host disease following experimental allogeneic hematopoietic cell transplantation. These data collectively characterize 3D genomic architecture of T cells in vivo and demonstrate biological and clinical implications for its disruption by cohesin releasing factor WAPL.

The 3D structure and function of digestive cathepsin L-like proteinases of Tenebrio molitor larval midgut

2012 ◽  
Vol 42 (9) ◽  
pp. 655-664 ◽  
Author(s):  
Daniela Beton ◽  
Cristiane R. Guzzo ◽  
Alberto F. Ribeiro ◽  
Chuck S. Farah ◽  
Walter R. Terra
Keyword(s):  
Cathepsin L ◽  
3D Structure ◽  
Tenebrio Molitor ◽  
Structure And Function ◽  
Larval Midgut ◽  
And Function

scholarly journals Structural Adaptation of Cold-Active RTX Lipase fromPseudomonassp. Strain AMS8 Revealed via Homology and Molecular Dynamics Simulation Approaches

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Mohd. Shukuri Mohamad Ali ◽  
Siti Farhanie Mohd Fuzi ◽  
Menega Ganasen ◽  
Raja Noor Zaliha Raja Abdul Rahman ◽  
Mahiran Basri ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Industrial Applications ◽  
Structure And Function ◽  
Molecular Engineering ◽  
Dynamics Simulation ◽  
Structural Adaptation ◽  
C Terminus ◽  
Different Temperatures ◽  
And Function ◽  
3D Molecular Structure

The psychrophilic enzyme is an interesting subject to study due to its special ability to adapt to extreme temperatures, unlike typical enzymes. Utilizing computer-aided software, the predicted structure and function of the enzyme lipase AMS8 (LipAMS8) (isolated from the psychrophilicPseudomonassp., obtained from the Antarctic soil) are studied. The enzyme shows significant sequence similarities with lipases fromPseudomonassp. MIS38 andSerratia marcescens. These similarities aid in the prediction of the 3D molecular structure of the enzyme. In this study, 12 ns MD simulation is performed at different temperatures for structural flexibility and stability analysis. The results show that the enzyme is most stable at 0°C and 5°C. In terms of stability and flexibility, the catalytic domain (N-terminus) maintained its stability more than the noncatalytic domain (C-terminus), but the non-catalytic domain showed higher flexibility than the catalytic domain. The analysis of the structure and function of LipAMS8 provides new insights into the structural adaptation of this protein at low temperatures. The information obtained could be a useful tool for low temperature industrial applications and molecular engineering purposes, in the near future.

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