1,721,007 research outputs found
Conformational switch of a flexible loop in human laminin receptor determines laminin-1 interaction
No full textThe 37/67-kDa human laminin receptor (LamR) is a cell surface protein that interacts with molecules located in the extra-cellular matrix. In particular, interactions between LamR and laminins play a major role in mediating changes in the cellular environment that affect cell adhesion, neurite outgrowth, tumor growth and metastasis. The exact interaction mode of laminin-1 and LamR is not fully understood. Laminin-1 is thought to bind to LamR through interaction with the so-called peptide G (residues 161–180) and the C-terminal helix (residues 205–229). Here we performed 100-ns atomistic force field-based molecular dynamics simulations to explore the structure and dynamics of LamR related to laminin-1 interactions. Our main finding is that loop 188–197 in the C-terminal region is highly flexible. It undergoes a major change resulting in a conformational switch that partially solvent exposes the R180 residue in the final part of the G peptide. So, R180 could contribute to laminin-1 binding. Projection of the simulations along the first two principal components also confirms the importance of this conformational switch in the LamR. This may be a basic prerequisite to clarify the key structural determinants of the interaction of LamR with laminin-1
Molecular Modelling Of BCRP (ABCG2) Multidrug Resistance Protein And Docking Of New Camptothecin Analogues
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Molecular dynamics study of a hyperthermophilic and a mesophilic Rubredoxin.
No full textIn recent years, increased interest in the origin of protein thermal stability has gained attention both for its possible role in understanding the forces governing the folding of a protein and for the design of new highly stable engineered biocatalysts. To study the origin of thermostability, we have performed molecular dynamics simulations of two rubredoxins, from the mesophile Clostridium pasteurianum and from the hyperthermophile Pyrococcus furiosus. The simulations were carried out at two temperatures, 300 and 373 K, for each molecule. The length of the simulations was within the range of 6–7.2 ns. The rubredoxin from the hyperthermophilic organism was more flexible than its mesophilic counterpart at both temperatures; however, the overall flexibility of both molecules at their optimal growth temperature was the same, despite 59% sequence homology. The conformational space sampled by both molecules was larger at 300 K than at 373 K. The essential dynamics analysis showed that the principal overall motions of the two molecules are significantly different. On the contrary, each molecule showed similar directions of motion at both temperatures
Episodic Ataxia Type 1 Mutations Affect Fast Inactivation of K+ Channels by a Reduction in Either Subunit Surface Expression or Affinity for Inactivation Domain
No full textEpisodic ataxia type 1 (EA1) is an autosomal dominant disorder characterized by continuous myokymia and episodic attacks of ataxia. Mutations in the gene KCNA1 that encodes the voltage-gated potassium channel Kv1.1 are responsible for EA1. In several brain areas, Kv1.1 coassembles with Kv1.4, which confers N-type inactivating properties to heteromeric channels. It is therefore likely that the rate of inactivation will be determined by the number of Kv1.4 inactivation particles, as set by the precise subunit stoichiometry. We propose that EA1 mutations affect the rate of N-type inactivation either by reduced subunit surface expression, giving rise to a reduced number of Kv1.1 subunits in heterotetramer Kv1.1-Kv1.4 channels, or by reduced affinity for the Kv1.4 inactivation domain. To test this hypothesis, quantified amounts of mRNA for Kv1.4 or Kv1.1 containing selected EA1 mutations either in the inner vestibule of Kv1.1 on S6 or in the transmembrane regions were injected into Xenopus laevis oocytes and the relative rates of inactivation and stoichiometry were determined. The S6 mutations, V404I and V408A, which had normal surface expression, reduced the rate of inactivation by a decreased affinity for the inactivation domain while the mutations I177N in S1 and E325D in S5, which had reduced subunit surface expression, increased the rate of N-type inactivation due to a stoichiometric increase in the number of Kv1.4 subunit
Phosphorylation, mg‐adp, and inhibitors differentially shape the conformational dynamics of the a‐loop of aurora‐a
Full text linkThe conformational state of the activation loop (A‐loop) is pivotal for the activity of most protein kinases. Hence, the characterization of the conformational dynamics of the A‐loop is important to increase our understanding of the molecular processes related to diseases and to support the discovery of small molecule kinase inhibitors. Here, we carry out a combination of molecular dynamics (MD) and essential dynamics (ED) analyses to fully map the effects of phosphorylation, ADP, and conformation disrupting (CD) inhibitors (i.e., CD532 and MLN8054) on the dynamics of the A‐loop of Aurora‐A. MD revealed that the stability of the A‐loop in an open conformation is enhanced by single phospho‐Thr‐288, while paradoxically, the presence of a second phosphoryla-tion at Thr‐287 decreases such stability and renders the A‐loop more fluctuant in time and space. Moreover, we found that this post‐translational modification has a significant effect on the direc-tion of the A‐loop motions. ED analysis suggests that the presence of the phosphate moiety induces the dynamics of Aurora‐A to sample two distinct energy minima, instead of a single large mini-mum, as in unphosphorylated Aurora‐A states. This observation indicates that the conformational distributions of Aurora‐A with both single and double phospho‐threonine modifications are re-markably different from the unphosphorylated state. In the closed states, binding of CD532 and MLN8054 inhibitors has the effect of increasing the distance of the N‐ and C‐lobes of the kinase domain of Aurora‐A, and the angle analysis between those two lobes during MD simulations showed that the N‐ and C‐lobes are kept more open in presence of CD532, compared to MLN8054. As the A‐loop is a common feature of Aurora protein kinases, our studies provide a general de-scription of the conformational dynamics of this structure upon phosphorylation and different ligands binding
The Structure of The Laminin Β1 Nonapeptide Probed Through Long-Timescale Temperature Replica-Exchange Molecular Dynamics Simulations in Explicit Solvent
No full textLaminin-1 is a member of a heterotrimeric glycoproteins family belonging to basement membrane.
These proteins interact with cell surface receptors involved in adhesion, proliferation, differentiation and angiogenesis processes. The laminin-1 β1 nonapeptide CDPGYIGSR, known also as peptide 11, from domain III of the β1 chain of laminin-1, has been identified as the putative primary binding site for the 67 kDa Laminin Receptor (LR).(1) Overexpression of LR showed strong correlations with poor clinical prognosis in several solid tumors. Because of its critical role in cancer progression, the potential laminin-1 bioactive conformation has been the focus of a number of structural and biological studies. Here, the conformational dynamics of peptide 11 was probed by temperature replica-exchange molecular dynamics (T-REMD) simulations in explicit solvent.(2-3) T-REMD simulations were completed starting from an initial mutated structure of the murine epidermal growth factor peptide (mEGF-(33–42 residues)). Each replica was run for 100 ns. The structural characters were studied based on parameters such as distributions of backbone dihedral angles, free energy surface, stability of folded structure, and favourite conformations. The results showed that the peptide 11 in water adopted two different
conformational states: the first state (A) was a bend ensemble with an open β-turn2–5 and nine hydrogen
bonds, the second state (B) was a bend ensemble with a open β-turn2-5 and five hydrogen bonds. These findings allowed us to define a pharmacophore model useful for the design of small molecules able to destabilize LR/laminin-1 interaction
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