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Wenjun Zheng, Zheng Liu
The ryanodine receptors (RyR) are essential to calcium signaling in striated muscles, and numerous disease mutations have been identified in two RyR isoforms, RyR1 in skeletal muscle and RyR2 in cardiac muscle. A deep understanding of the activation/regulation mechanisms of RyRs has been hampered by the shortage of high-resolution structures and dynamic information for this giant tetrameric complex in different functional states. Toward elucidating the molecular mechanisms of disease mutations in RyRs, we performed molecular dynamics simulation of the N-terminal domain (NTD) which is not only the best-resolved structural component of RyRs, but also a hotspot of disease mutations...
May 15, 2017: Proteins
Laith Hisham Harb, Mahreen Arooj, Alice Vrielink, Ricardo L Mancera
Cholesterol oxidase (ChOx) is a flavoenzyme that oxidises and isomerises cholesterol (CHL) to form cholest-4-en-3-one. Molecular docking and molecular dynamics simulations were conducted to predict the binding interactions of CHL in the active site. Several key interactions (E361-CHL, N485-FAD and H447-CHL) were identified and which are likely to determine the correct positioning of CHL relative to flavin-adenine dinucleotide (FAD). Binding of CHL also induced changes in key residues of the active site leading to the closure of the oxygen channel...
May 15, 2017: Proteins
Abdallah Sayyed-Ahmad, Priyanka Prakash, Alemayehu A Gorfe
Despite years of study the structural or dynamical basis for the differential reactivity and oncogenicity of Ras isoforms and mutants remains unclear. In this study, we investigated the effects of amino acid variations on the structure and dynamics of wild type and oncogenic mutants G12D, G12V and G13D of H- and K-Ras proteins. Based on data from µs-scale molecular dynamics simulations, we show that the overall structure of the proteins remains similar but there are crucial differences in dynamics and interaction networks...
May 12, 2017: Proteins
Chenxiao Zhao, Baoping Ling, Lihua Dong, Yongjun Liu
Porphyromonas gingivalis peptidylarginine deiminase (PPAD) catalyzes the citrullination of peptidylarginine, which plays a critical role in the rheumatoid arthritis (RA) and gene regulation. For a better understanding of citrullination mechanism of PPAD, it is required to establish the protonation states of active site cysteine, which is still a controversial issue for the members of guanidino-group modifying enzyme superfamily. In this work, we firstly explored the transformation between the two states: State N (both C351 and H236 are neutral) and State I (both residues exist as a thiolate-imidazolium ion pair), and then investigated the citrullination reaction of peptidylarginine, using a combined QM/MM approach...
May 9, 2017: Proteins
Prerna Priya, Atanu Maity, Shubhra Ghosh Dastidar
Bcl-xl protein has a long unstructured loop attached to its structured region which joins two helices. The necessity to have this unstructured segment in Bcl-xl is not yet understood. To what extent the unstructured segment can influence the dynamics of the structured region of protein, with potential to influence the function, has been investigated in this work. Molecular dynamics simulation and principal component analysis show how the loop affects the internal motions of the protein, particularly its ligand binding pocket...
May 9, 2017: Proteins
Maryam Azimzadeh Irani, Srinivasaraghavan Kannan, Chandra Verma
The Epidermal Growth Factor Receptor (EGFR) is a tyrosine kinase protein, overexpressed in several cancers. The extracellular domain of EGFR is known to be heavily glycosylated. Growth factor (mostly Epidermal Growth Factor or EGF) binding activates EGFR. This occurs by inducing the transition from the autoinhibited tethered conformation to an extended conformation of the monomeric form of EGFR and by stabilizing the flexible pre-formed dimer. Activated EGFR adopts a back-to-back dimeric conformation after binding of another homologous receptor to its extracellular domain as the dimeric partner...
May 9, 2017: Proteins
Karen T Schomburg, Eva Nittinger, Agnes Meyder, Stefan Bietz, Nadine Schneider, Gudrun Lange, Robert Klein, Matthias Rarey
Reliable computational prediction of protein side chain conformations and the energetic impact of amino acid mutations are key aspects for the optimization of biotechnological relevant enzymatic reactions using structure-based design. By improving the protein stability higher yields can be achieved. In addition, tuning the substrate selectivity of an enzymatic reaction by directed mutagenesis can lead to higher turnover rates. This work presents a novel approach to predict the conformation of a side chain mutation along with the energetic effect on the protein structure...
May 9, 2017: Proteins
Dror Tobi
A new algorithm for comparison of protein dynamics is presented. Compared protein structures are superposed and their modes of motions are calculated using the Anisotropic Network Model. The obtained modes are aligned using the dynamic programming algorithm of Needleman and Wunsch, commonly used for sequence alignment. Dynamical comparison of Hemoglobin in the T and R2 states reveals that the dynamics of the allosteric effector 2,3-Bisphosphoglycerate binding site is different in the two states. These differences can contribute to the selectivity of the effector to the T state...
April 29, 2017: Proteins
Farai I Rusinga, David D Weis
The effects of macromolecular crowding on the transient structure of intrinsically disordered proteins is not well-understood. Crowding by biological molecules inside cells could modulate transient structure and alter IDP function. Volume exclusion theory and observations of structured proteins suggest that IDP transient structure would be stabilized by macromolecular crowding. Amide hydrogen exchange (HX) of IDPs in highly concentrated polymer solutions would provide valuable insights into IDP transient structure under crowded conditions...
April 20, 2017: Proteins
Xiong An Lee, Chandra Verma, Adelene Y L Sim
Mdm2 and MdmX share high structural similarity in their N-terminal domains, yet dual inhibitors are challenging to design due to differences in the conformations of the binding pockets, and notably of the proposed gatekeeper residue, Y100/99. Analysis of crystal structures and molecular dynamics (MD) simulations of complexes of Mdm2 and MdmX resulted in the identification of a water molecule with a long residence time that appears to be modulated by the conformation of Y100/99. These observations lead us to speculate that dual inhibitors either i) stabilize both Mdm2 and MdmX with Y100/99 in the open conformation typically seen in complexes of Mdm2 with p53, or ii) the dual inhibitors are agnostic to the conformation of Y100/99...
April 20, 2017: Proteins
Štefan Janeček, Katarína Majzlová, Birte Svensson, E Ann MacGregor
Within the CAZy database, there are 81 carbohydrate-binding module (CBM) families. A CBM represents a non-catalytic domain in a modular arrangement of glycoside hydrolases (GHs). The present in silico study has been focused on starch-binding domains from the family CBM41 that are usually part of pullulanases from the α-amylase family GH13. Currently there are more than 1,600 sequences classified in the family CBM41, almost exclusively from Bacteria, and so a study was undertaken in an effort to divide the members into relevant groups (subfamilies) and also to contribute to the evolutionary picture of family CBM41...
April 20, 2017: Proteins
Bijendra Khadka, Radhey S Gupta
Homologs of the phosphatidylinositol-4-phosphate-5-kinase (PIP5K), which controls a multitude of essential cellular functions, contain a 8 aa insert in a conserved region that is specific for the Saccharomycetaceae family of fungi. Using structures of human PIP4K proteins as templates, structural models were generated of the Saccharomyces cerevisiae and human PIP5K proteins. In the modeled S. cerevisiae PIP5K, the 8 aa insert forms a surface exposed loop, present on the same face of the protein as the activation loop of the kinase domain...
April 13, 2017: Proteins
Guanya Peng, Alastair G McEwen, Vincent Olieric, Celine Schmitt, Sebastien Albrecht, Jean Cavarelli, Celine Tarnus
Aminopeptidases are ubiquitous hydrolases that cleave the N-terminal residues of proteins and oligopeptides. They are broadly distributed throughout all kingdoms of life and have been implicated in a wide variety of physiological processes, including viral infection, parasite metabolism, protein processing, regulation of peptide hormones, and cancer cell proliferation. Members of the M1 family, also termed gluzincins, are defined by two highly conserved motifs in the catalytic domain: a zinc binding motif, HEXXH-(X18)-E; and an exopeptidase motif, GXMEN...
April 6, 2017: Proteins
Sambit Kumar Mishra, Kannan Sankar, Robert L Jernigan
It is known that over half of the proteins encoded by most organisms function as oligomeric complexes. Oligomerization confers structural stability and dynamics changes in proteins. We investigate the effects of oligomerization on protein dynamics and its functional significance for a set of 145 multimeric proteins. Using coarse-grained elastic network models, we inspect the changes in residue fluctuations upon oligomerization and then compare with residue conservation scores to identify the functional significance of these changes...
April 6, 2017: Proteins
M L Gerth, Y Liu, W Jiao, X-X Zhang, E N Baker, J S Lott, P B Rainey, J M Johnston
Cupins form one of the most functionally diverse superfamilies of proteins, with members performing a wide range of catalytic, non-catalytic, and regulatory functions. HutD is a predicted bicupin protein that is involved in histidine utilization (Hut) in Pseudomonas species. Previous genetic analyses have suggested that it limits the upper level of Hut pathway expression, but its mechanism of action is unknown. Here, we have determined the structure of PfluHutD at 1.74 Å resolution in several crystallization conditions, and identified N-formyl-L-glutamate (a Hut pathway intermediate) is a potential ligand in vivo...
April 6, 2017: Proteins
Md Munan Shaik, Nicholus Bhattacharjee, Mikolaj Feliks, Kenneth K-S Ng, Martin J Field
Norovirus (NV) RNA-dependent RNA polymerase (RdRP) is essential for replicating the genome of the virus, which makes this enzyme a key target for the development of antiviral agents against NV gastroenteritis. In this work, a complex of NV RdRP bound to manganese ions and an RNA primer-template duplex was investigated using X-ray crystallography and hybrid quantum chemical/molecular mechanical simulations. Experimentally, the complex crystallized in a tetragonal crystal form. The nature of the primer/template duplex binding in the resulting structure indicates that the complex is a closed back-tracked state of the enzyme, in which the 3'-end of the primer occupies the position expected for the post-incorporated nucleotide before translocation...
April 6, 2017: Proteins
Hanwool Yoon, Arieh Warshel
Pol η belongs to the important Y family of DNA polymerases that can catalyze translesion synthesis across sites of damaged DNA. This activity involves the reduced fidelity of Pol η for 8-oxo-7,8-dhyedro-2'-deoxoguanosin(8-oxoG). The fundamental interest in Pol η has grown recently with the demonstration of the importance of a 3rd Mg2+ ion. The current work explores both the fidelity of Pol η and the role of the 3rd metal ion, by using empirical valence bond (EVB) simulations. The simulations reproduce the observed trend in fidelity and shed a new light on the role of the 3rd metal ion...
April 6, 2017: Proteins
Kyrylo Bessonov, Kenrick A Vassall, George Harauz
The molecular details of the association between the human Fyn-SH3 domain, and the fragment of 18.5-kDa myelin basic protein (MBP) spanning residues S38-S107 (denoted as xα2-peptide, murine sequence numbering), were studied in silico via docking and molecular dynamics over 50-ns trajectories. The results show that interaction between the two proteins is energetically favorable and heavily-dependent on the MBP proline-rich region (P93-P98) in both aqueous and membrane environments. In aqueous conditions, the xα2-peptide/Fyn-SH3 complex adopts a "sandwich"-like structure...
April 5, 2017: Proteins
Emma M Rath, Anthony P Duff, Elliot P Gilbert, Greg Doherty, Robert B Knott, W Bret Church
The anti-cancer complex, BAMLET, has intriguing broad-spectrum anti-cancer activity. Although aspects of BAMLET's anti-cancer mechanism are still not known, it is understood that it involves the oleic acid or oleate component of BAMLET being preferentially released into cancer cell membranes leading to increased membrane permeability and lysis. The structure of the protein component of BAMLET has previously been elucidated by small angle X-ray scattering (SAXS) to be partially unfolded and dramatically enlarged...
April 5, 2017: Proteins
Vanesa Olivares-Illana, Hector Riveros-Rosas, Nallely Cabrera, Marietta Tuena de Gómez-Puyou, Ruy Pérez-Montfort, Miguel Costas, Armando Gómez-Puyou
Triosephosphate isomerase (TIM) is a ubiquitous enzyme, which appeared early in evolution. TIM is responsible for obtaining net ATP from glycolysis and producing an extra pyruvate molecule for each glucose molecule, under aerobic and anaerobic conditions. It is placed in a metabolic crossroad that allows a quick balance of the triose phosphate aldolase produced by glycolysis, and is also linked to lipid metabolism through the alternation of glycerol-3-phosphate and the pentose cycle. TIM is one of the most studied enzymes with more than 199 structures deposited in the PDB...
April 5, 2017: Proteins
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