Search results for "Homology modeling"
showing 10 items of 30 documents
The Binding Mechanism of Epolactaene to Hsp60 Unveiled by in Silico Modelling
2016
Molecular Dynamics (MD) simulations and DFT/MM calculations were performed in order to rationalize available experimental results and to provide structural details on the binding mechanism of Epolactaene (EPO) to the 60 KDa Heat Shock Protein (Hsp60). The available crystal structure of Hsp60 represents the last step of the chaperone folding cycle, while the Hsp60-EPO complex was obtained by using a homology model of Hsp60, in order to simulate a state related to the beginning of the folding cycle (Rs1). The results of MD simulations point out that EPO shows the highest binding affinity for the empty ATP binding site. The presence of ATP opens a channel that allows the entrance of both EPO d…
In Silico Insights towards the Identification of NLRP3 Druggable Hot Spots
2019
NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) activation has been linked to several chronic pathologies, including atherosclerosis, type-II diabetes, fibrosis, rheumatoid arthritis, and Alzheimer’s disease. Therefore, NLRP3 represents an appealing target for the development of innovative therapeutic approaches. A few companies are currently working on the discovery of selective modulators of NLRP3 inflammasome. Unfortunately, limited structural data are available for this target. To date, MCC950 represents one of the most promising noncovalent NLRP3 inhibitors. Recently, a possible region for the binding of MCC950 to the NLRP3 protein was described but no details were …
Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study
2018
International audience; Nicotinic acetylcholine receptors, belonging to the Cys-loop super-family of ligand-gated ion channels (LGICs), are membrane proteins present in neurons and at neuromuscular junctions. They are responsible for signal transmission, and their function is regulated by neurotransmitters, agonists and antagonists drugs. A detailed knowledge of their conformational transition in response to ligand binding is critical to understand the basis of ligand-receptor interaction, in view of new pharmacological approaches to control receptor activity. However, the scarcity of experimentally derived structures of human channels makes this perspective extremely challenging. To contri…
A possible desensitized state conformation of the human α7 nicotinic receptor: A molecular dynamics study
2017
International audience; The determination of the conformational states corresponding to diverse functional roles of ligand gated ion channels is subject of intense investigation with various techniques, from X-rays structure determination to electrophysiology and computational modeling. Even with a certain number of structures becoming recently available, only few major structural features distinguishing conductive open channel from the non conductive resting protein have been highlighted, while high-resolution details are still missing. The characterization of the desensitized conformation(s) is even more complex, and only few specific characteristics have been identified. Furthermore, exp…
In Silico Conformational Features of Botulinum Toxins A1 and E1 According to Intraluminal Acidification
2022
International audience; Although botulinum neurotoxins (BoNTs) are among the most toxic compounds found in nature, their molecular mechanism of action is far from being elucidated. A key event is the conformational transition due to acidification of the interior of synaptic vesicles, leading to translocation of the BoNT catalytic domain into the neuronal cytosol. To investigate these conformational variations, homology modeling and atomistic simulations are combined to explore the internal dynamics of the sub-types BoNT/A1 (the most-used sub-type in medical applications) and BoNT/E1 (the most kinetically efficient sub-type). This first simulation study of di-chain BoNTs in closed and open s…
Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics
2021
Graphical abstract
NMR and homology modeling studies of copper(II)-halocyanin from Natronobacterium pharaonis bacteria
2004
Abstract Halocyanin from the haloalkaliphilic archaean Natronobacterium pharaonis is a peripheral membrane type 1 blue copper protein with a single polypeptide chain of 163 amino acid residues. Halocyanin participates as putative electron carrier protein associated to an electron acceptor role for a terminal oxidase and has the lowest redox potential value reported to date for a BCP. NMR studies and homology modeling calculations were performed to evaluate the electronic properties of Cu(II)-halocyanin from Natronobacterium pharaonis . The copper coordination site properties of Cu(II)-halocyanin are discussed. The 1 H NMR spectra, isotropic chemical shifts and relaxation times for halocyani…
Amino acids in the second transmembrane helix of the Lhca4 subunit are important for formation of stable heterodimeric light-harvesting complex LHCI-…
2007
Photosynthetic light-harvesting complexes (LHCs) are assembled from apoproteins (Lhc proteins) and non-covalently attached pigments. Despite a considerable amino acid sequence identity, these proteins differ in their oligomerization behavior. To identify the amino acid residues determining the heterodimerization of Lhca1 and Lhca4 to form LHCI-730, we mutated the poorly conserved second transmembrane helix of the two subunits. Mutated genes were expressed in Escherichia coli and the resultant proteins were refolded in vitro and subsequently analyzed by gel electrophoresis. Replacement of the entire second helix in Lhca4 by the one of Lhca3 abolished heterodimerization, whereas it had no eff…
Establishment and functional validation of a structural homology model for human DNA methyltransferase 1
2003
Changes in DNA methylation patterns play an important role in tumorigenesis. The DNA methyltransferase 1 (DNMT1) protein represents a major DNA methyltransferase activity in human cells and is therefore a prominent target for experimental cancer therapies. However, there are only few available inhibitors and their high toxicity and low specificity have so far precluded their broad use in chemotherapy. Based on the strong conservation of catalytic DNA methyltransferase domains we have used a homology modeling approach to determine the three-dimensional structure of the DNMT1 catalytic domain. Our results suggest an overall structural conservation with other DNA methyltransferases but also in…
Engineering of a bacterial tyrosinase for improved catalytic efficiency towards D-tyrosine using random and site directed mutagenesis approaches
2013
The tyrosinase gene from Ralstonia solanacearum (GenBank NP518458) was subjected to random mutagenesis resulting in tyrosinase variants (RVC10 and RV145) with up to 3.2-fold improvement in kcat, 5.2-fold lower Km and 16-fold improvement in catalytic efficiency for D-tyrosine. Based on RVC10 and RV145 mutated sequences, single mutation variants were generated with all variants showing increased kcat for D-tyrosine compared to the wild type (WT). All single mutation variants based on RV145 had a higher kcat and Km value compared to the RV145 and thus the combination of four mutations in RV145 was antagonistic for turnover, but synergistic for affinity of the enzyme for D-tyrosine. Single muta…