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Vincenzo Carbone, Linley R Schofield, Carrie Sang, Andrew J Sutherland-Smith, Ron S Ronimus
The crystal structure of UDP-N-acetylglucosamine 4-epimerase (UDP-GlcNAc 4-epimerase; WbpP; EC, from the archaeal methanogen Methanobrevibacter ruminantium strain M1, was determined to a resolution of 1.65 Å. The structure, with a single monomer in the crystallographic asymmetric unit, contained a conserved N-terminal Rossmann fold for nucleotide binding and an active site positioned in the C-terminus. UDP-GlcNAc 4-epimerase is a member of the short-chain dehydrogenases/reductases superfamily, sharing sequence motifs and structural elements characteristic of this family of oxidoreductases and bacterial 4-epimerases...
September 22, 2018: Proteins
Vinícius G Contessoto, Vinícius M de Oliveira, Bruno R Fernandes, Gabriel G Slade, Vitor B P Leite
The TKSAMC is a web server which calculates protein charge-charge interactions via the Tanford-Kirkwood Surface Accessibility model with the Monte Carlo method for sampling different protein protonation states. The optimization of charge-charge interactions via directed mutations has successfully enhanced the thermal stability of different proteins and could be a key to protein engineering improvement. The server presents the electrostatic free energy contribution of each polar-charged residue to the protein native state stability...
September 14, 2018: Proteins
B W J Irwin, Siniša Vukovič, M C Payne, Mohammad ElGamacy, P-L Chau
We have performed docking simulations on GABARAP interacting with the GABA type A receptor using SwarmDock. We have also used a novel method to study hydration sites on the surface of these two proteins; this method identifies regions around proteins where desolvation is relatively easy, and these are possible locations where proteins can bind each other. There is a high degree of consistency between the predictions of these two methods. Moreover, we have also identified binding sites on GABARAP for other proteins, and listed possible binding sites for as yet unknown proteins on both GABARAP and the GABA type A receptor intracellular domain...
September 14, 2018: Proteins
R N V Krishna Deepak, Ahmad Abdullah, Priti Talwar, Hao Fan, Palaniyandi Ravanan
The regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted...
September 8, 2018: Proteins
Blessing Mabate, Tawanda Zininga, Lebogang Ramatsui, Stanley Makumire, Ikechukwu Achilonu, Heini W Dirr, Addmore Shonhai
Plasmodium falciparum, the main agent of malaria expresses six members of the heat shock protein 70 (Hsp70) family. Hsp70s serve as protein folding facilitators in the cell. Amongst the six Hsp70 species that P. falciparum expresses, Hsp70-x (PfHsp70-x), is partially exported to the host red blood cell where it is implicated in host cell remodeling. Nearly 500 proteins of parasitic origin are exported to the parasite-infected red blood cell (RBC) along with PfHsp70-x. The role of PfHsp70-x in the infected human RBC remains largely unclear...
September 5, 2018: Proteins
Marharyta Petukh, Igor B Zhulin
The Niemann-Pick type C1 (NPC1) protein is a large transmembrane protein located in lysosomes/endosomes. NPC1 binds cholesterol (CLR) and transports it to cellular membrane and endoplasmic reticulum. Mutations in NPC1 cause Niemann-Pick type C (NPC) disease, a rare autosomal disorder characterized by intracellular accumulations of CLR and subsequent neurodegeneration leading to premature death. Among known disease-causing mutations in NPC1, Q92R is the one that is located in the N-terminal cholesterol-binding domain (NTD)...
September 5, 2018: Proteins
Rotem Aharoni, Dror Tobi
Myoglobin and Hemoglobin are globular hemeproteins, when the former is a monomer and the latter a heterotetramer. Despite the structural similarity of Myoglobin to α and β subunits of Hemoglobin, there is a functional difference between the two proteins, owing to the quaternary structure of Hemoglobin. The effect of the quaternary structure of Hemoglobin on the intrinsic dynamics of its subunits is explored by dynamical comparison of the two proteins. Anisotropic Network Model modes of motion were calculated for Hemoglobin and Myoglobin...
September 5, 2018: Proteins
Kheerthana Duraivelan, Aditya J Basak, Amit Ghosh, Dibyendu Samanta
Cell adhesion molecules such as nectins and cadherins play important role in the formation of adherens junction. While nectins interact through their extracellular domains in both homophilic and heterophilic manner among themselves, extracellular domains of cadherins participate only in homophilic fashion to mediate cell-cell adhesion. It is well established that nectins recruit cadherins in the adhesion sites through an interplay of adaptor molecules in the cytoplasmic side thereby increasing the effective concentration of both the adhesion molecules on the cell surface...
September 5, 2018: Proteins
Kannan Sankar, Stanley R Krystek, Stephen M Carl, Tyler Day, Johannes K X Maier
Protein aggregation is a phenomenon that has attracted considerable attention within the pharmaceutical industry from both a developability standpoint (to ensure stability of protein formulations) and from a research perspective for neurodegenerative diseases. Experimental identification of aggregation behavior in proteins can be expensive; and hence, the development of accurate computational approaches is crucial. The existing methods for predicting protein aggregation rely mostly on the primary sequence and are typically trained on amyloid-like proteins...
August 30, 2018: Proteins
Xiaoying Zhang, Qingzhan Yang, Qingya Shen, Jimin Zheng, Zongchao Jia
Nucleotide binding proteins are involved in many important cellular processes and form one of the largest protein families. Traditionally, the identification of nucleotide binding motif, such as the ATP binding P-loop, has relied on the comparison of protein sequences, consideration of the function of each of the proteins and the identification of signature motifs within the sequence. Sometimes, it is difficult to identify nucleotide binding proteins based on sequence alignment because of increased evolutionary distances...
August 30, 2018: Proteins
Gordon Wells, Hongjie Yuan, Miranda J McDaniel, Hirofumi Kusumoto, James P Snyder, Dennis C Liotta, Stephen F Traynelis
N-methyl-D-aspartate (NMDA) receptors are transmembrane glutamate-binding ion channels that mediate neurotransmission in mammals. NMDA receptor subunits are tetrameric complexes of GluN1 and GluN2A-D subunits, encoded by the GRIN gene family. Of these subunits, GluN2B is suggested to be required for normal development of the central nervous system. A mutation identified in a patient with developmental delay, E413G, resides in the GluN2B ligand-binding domain and substantially reduces glutamate potency by an unknown mechanism...
August 30, 2018: Proteins
Xiao-Xuan Shi, Yi-Ben Fu, Si-Kao Guo, Peng-Ye Wang, Hong Chen, Ping Xie
Changes of affinity of kinesin head to microtubule regulated by changes in the nucleotide state are essential to processive movement of kinesin on microtubule. Here, using all-atom molecular dynamics simulations we show that besides the nucleotide state, large conformational changes of microtubule-tubulin heterodimers induced by strong interaction with the head in strongly binding state are also indispensable to regulate the affinity of the head to the tubulin. In strongly binding state the high affinity of the head to microtubule arises largely from mutual conformational changes of the microtubule and head induced by the specific interaction between them via an induced-fit mechanism...
August 22, 2018: Proteins
Fanchi Meng, Lukasz Kurgan
Intrinsically disordered regions lack stable structure in their native conformation but are nevertheless functional and highly abundant, particularly in Eukaryotes. Disordered moonlighting regions (DMRs) are intrinsically disordered regions that carry out multiple functions. DMRs are different from moonlighting proteins that could be structured and that are annotated at the whole-protein level. DMRs cannot be identified by current predictors of functions of disorder that focus on specific functions rather than multifunctional regions...
August 11, 2018: Proteins
Rebecca Vera, Melissa Synsmir, Sarah Ojinnaka, David A Snyder
Knowledge of protein flexibility is crucial to understanding protein function. However, probing protein flexibility by either experiment or computational simulations is a difficult process. In particular, many computational approaches to understanding protein flexibility require an experimentally determined protein structure. The Conformationally Restrained Contact Map (CoRe-CMap) approach reported here couples protein disorder predictions with protein structure predictions and only requires sequence data to predict protein flexibility...
August 11, 2018: Proteins
Victor Jun Yu Lim, Weina Du, Yu Zong Chen, Hao Fan
G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking. Thus, we evaluated the virtual screening performance of homology models of human GPCRs with respect to the corresponding crystal structures. Among the 19 GPCRs involved in this study, we observed that 10 GPCRs have homology models that have better or comparable performance with respect to the corresponding X-ray structures, making homology models a viable choice for virtual screening...
July 27, 2018: Proteins
Burak Erman
We present a computational model that allows for rapid prediction of correlations among a set of residue pairs when the fluctuations of another set of residues are perturbed. The simple theory presented here is based on the knowledge of the fluctuation covariance matrix only. In this sense, the theory is model independent and therefore universal. Perturbation of any set of fluctuations and the resulting response of the remaining set are calculated using conditional probabilities of a multivariate normal distribution...
July 27, 2018: Proteins
Sameer Hassan, Sanjay Kumar Srikakulam, Yuvaraj Chandramohan, Manonanthini Thangam, Soundharrya Muthukumar, P K Gayathri Devi, Luke Elizabeth Hanna
HIV protease, an essential enzyme for viral particle maturation, is an important drug target of HIV. Its structural conformation is a key determinant of both biological function as well as efficient binding of protease inhibitor molecules. In the present study we analyzed 471 crystal structures of HIV-1 protease to understand the conformational changes induced by mutations or binding of various ligands and substrates. We performed principal component analysis on the ensembles of the HIV-1 protease structures to explore the conformational landscapes...
July 27, 2018: Proteins
A Paiardini, F Mantoni, G Giardina, A Paone, G Janson, L Leoni, G Rampioni, F Cutruzzolà, S Rinaldo
Nutrients such as amino acids play key roles in shaping the metabolism of microorganisms in natural environments and in host-pathogen interactions. Beyond taking part to cellular metabolism and to protein synthesis, amino acids are also signalling molecules able to influence group behaviour in microorganisms, such as biofilm formation. This lifestyle switch involves complex metabolic reprogramming controlled by local variation of the second messenger 3', 5'-cyclic diguanylic acid (c-di-GMP). The intracellular levels of this dinucleotide are finely tuned by the opposite activity of dedicated diguanylate cyclases (GGDEF signature) and phosphodiesterases (EAL and HD-GYP signatures), which are usually allosterically controlled by a plethora of environmental and metabolic clues...
July 24, 2018: Proteins
Pouria Dasmeh, Adrian W R Serohijos
The extent of non-additive interaction among mutations or epistasis reflects the ruggedness of the fitness landscape, the mapping of genotype to reproductive fitness. In protein evolution, there is strong support for the importance and prevalence of epistasis but the quantitative and relative contribution of various factors to epistasis are poorly known. Here, we determine the contribution of selection for folding stability to epistasis in protein evolution. By combining theoretical estimates of the rates of molecular evolution and the non-linear mapping between protein folding thermodynamics and fitness, we show that the simple selection for folding stability imposes at least ~30% to ~40% epistasis in long-term protein evolution...
July 24, 2018: Proteins
Andrei Santos Siqueira, Alex Ranieri Jerônimo Lima, Delia Cristina Figueira Aguiar, Alberdan Silva Santos, João Lídio da Silva Gonçalves Vianez Júnior, Evonnildo Costa Gonçalves
Lectins are proteins of nonimmune origin, which are capable of recognizing and binding to glycoconjugate moieties. Some of them can block the interaction of viral glycoproteins to the host cell receptors acting as antiviral agents. Although cyanobacterial lectins have presented broad biotechnological potential, little research has been directed to Amazonian Cyanobacterial diversity. In order to identify new antiviral lectins, we performed genomic analysis in seven cyanobacterial strains from Coleção Amazônica de Cianobactérias e Microalgas (CACIAM)...
July 23, 2018: Proteins
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