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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 3(rd) Mg(2+) ion. The current work explores both the fidelity of Pol η and the role of the 3(rd) 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 3(rd) 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
Samuel W K Wong, Jun S Liu, S C Kou
In the prediction of protein structure from amino acid sequence, loops are challenging regions for computational methods. Since loops are often located on the protein surface, they can have significant roles in determining protein functions and binding properties. Loop prediction without the aid of a structural template requires extensive conformational sampling and energy minimization, which are computationally difficult. In this article we present a new de novo loop sampling method, the Parallely-filtered Energy Targeted All-atom Loop Sampler (PETALS) to rapidly locate low energy conformations...
April 5, 2017: Proteins
Tahsin F Kellici, Thomas Mavromoustakos, Dieter Jendrossek, Anastassios C Papageorgiou
An open and a closed conformation of a surface loop in PhaZ7 extracellular poly(3-hydroxybutyrate) depolymerase were identified in two high resolution crystal structures of a PhaZ7 Y105E mutant. Molecular dynamics (MD) simulations revealed high root mean square fluctuations (RMSF) of the 281-295 loop, in particular at residue Asp289 (RMSF 7.62 Å). Covalent docking between a 3-hydroxybutyric acid trimer and the catalytic residue Ser136 showed that the binding energy of the substrate is significantly more favourable in the open loop conformation compared to that in the closed loop conformation...
April 3, 2017: Proteins
Mengya Chai, Bo Liu, Fude Sun, Peng Wei, Peng Chen, Lida Xu, Shi-Zhong Luo
Kit ligand (KITL) plays important roles in cell proliferation, differentiation, and survival via interaction with its receptor Kit. The previous studies demonstrated that KITL formed a noncovalent homodimer through transmembrane (TM) domain; however, the undergoing mechanism of transmembrane association that determines KITL TM dimerization is still not clear. Herein, molecular dynamics (MD) simulation strategy and TOXCAT assay were combined to characterize the dimerization interface and structure of KITL TM in details...
April 3, 2017: Proteins
Didier Barradas-Bautista, Iain H Moal, Juan Fernández-Recio
Protein-protein interactions play fundamental roles in biological processes including signaling, metabolism and trafficking. While the structure of a protein complex reveals crucial details about the interaction, it is often difficult to acquire this information experimentally. As the number of interactions discovered increases faster than they can be characterized, protein-protein docking calculations may be able to reduce this disparity by providing models of the interacting proteins. Rigid-body docking is a widely used docking approach, and is often capable of generating a pool of models within which a near-native structure can be found...
March 25, 2017: Proteins
Richa Mudgal, Narayanaswamy Srinivasan, Nagasuma Chandra
Functional annotation is seldom straightforward with complexities arising due to functional divergence in protein families or functional convergence between non-homologous protein families, leading to mis-annotations. An enzyme may contain multiple domains and not all domains may be involved in a given function, adding to the complexity in function annotation. To address this, we use binding site information from bound cognate ligands and catalytic residues, since it can help in resolving fold-function relationships at a finer level and with higher confidence...
March 25, 2017: Proteins
Saurav Mallik, Sudip Kundu
Is the order in which biomolecular subunits self-assemble into functional macromolecular complexes imprinted in their sequence-space? Here we demonstrate that the temporal order of macromolecular complex self-assembly can be efficiently captured using the landscape of residue-level co-evolutionary constraints. This predictive power of co-evolutionary constraints is irrespective of the structural, functional and phylogenetic classification of the complex and of the stoichiometry and quaternary arrangement of the constituent monomers...
March 25, 2017: Proteins
Cristian Regep, Guy Georges, Jiye Shi, Bojana Popovic, Charlotte M Deane
The H3 loop in the Complementary Determining Region (CDR) of antibodies plays a key role in their ability to bind the diverse space of potential antigens. It is also exceptionally difficult to model computationally causing a significant hurdle for in-silico development of antibody biotherapeutics. In this paper we show that most H3s have unique structural characteristics which may explain why they are so challenging to model. We found that over 75% of H3 loops do not have a sub-Angstrom structural neighbour in the non-antibody world...
March 25, 2017: Proteins
Faezeh Kargar, Saeed Emadi, Hossein Fazli
The behavior of a single Aβ40 molecule within a dipalmitoylphosphatidylcholine (DPPC) bilayer was studied by all-atom molecular dynamics simulations. The effect of membrane structure was investigated on Aβ40 behavior, secondary structure and insertion depth. Simulations were performed at three temperatures (323, 310 and 300 K) to probe three different bilayer fluidities. Results show that at all above temperatures the peptide contains two short helices, coil, bend and turn structures. At 300 K, the peptide contains a region with β structure in C-terminal region...
March 25, 2017: Proteins
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