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Protein interface prediction

Aleš Hnízda, Milan Fábry, Takaya Moriyama, Petr Pachl, Michael Kugler, Vítězslav Brinsa, David B Ascher, William L Carroll, Petr Novák, Markéta Žaliová, Jan Trka, Pavlína Řezáčová, Jun J Yang, Václav Veverka
Activating mutations in NT5C2, a gene encoding cytosolic purine 5'-nucleotidase (cN-II), confer chemoresistance in relapsed acute lymphoblastic leukemia. Here we show that all mutants became independent of allosteric effects of ATP and thus constitutively active. Structural mapping of mutations described in patients demonstrates that 90% of leukemia-specific allelles directly affect two regulatory hotspots within the cN-II molecule-the helix A region: residues 355-365, and the intersubunit interface: helix B (232-242) and flexible interhelical loop L (400-418)...
February 25, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Sayan Poddar, Devlina Chakravarty, Pinak Chakrabarti
Characterization and prediction of the DNA-biding regions in proteins are essential for our understanding of how proteins recognize/bind DNA. We analyze the unbound (U) and the bound (B) forms of proteins from the protein-DNA docking benchmark that contains 66 binary protein-DNA complexes along with their unbound counterparts. Proteins binding DNA undergo greater structural changes on complexation (in particular, those in the enzyme category) than those involved in protein-protein interactions (PPI). While interface atoms involved in PPI exhibit an increase in their solvent-accessible surface area (ASA) in the bound form in the majority of the cases compared to the unbound interface, protein-DNA interactions indicate increase and decrease in equal measure...
March 9, 2018: Nucleic Acids Research
Moritz Horn, Virginia Kroef, Kira Allmeroth, Nicole Schuller, Stephan Miethe, Martin Peifer, Josef M Penninger, Ulrich Elling, Martin S Denzel
Forward genetic screens in haploid mammalian cells have recently emerged as powerful tools for the discovery and investigation of recessive traits. Use of the haploid system provides unique genetic tractability and resolution. Upon positive selection, these screens typically employ analysis of loss-of-function (LOF) alleles and are thus limited to non-essential genes. Many relevant compounds, including anti-cancer therapeutics, however, target essential genes, precluding positive selection of LOF alleles. Here, we asked whether the use of random and saturating chemical mutagenesis might enable screens that identify essential biological targets of toxic compounds...
February 9, 2018: Oncotarget
Paula G Slater, Sebastian E Gutierrez-Maldonado, Katia Gysling, Carlos F Lagos
The corticotropin-releasing factor (CRF) system is a key mediator of the stress response and addictive behavior. The CRF system includes four peptides: The CRF system includes four peptides: CRF, urocortins I-III, CRF binding protein (CRF-BP) that binds CRF with high affinity, and two class B G-protein coupled receptors CRF1 R and CRF2 R. CRF-BP is a secreted protein without significant sequence homology to CRF receptors or to any other known class of protein. Recently, it has been described a potentiation role of CRF-BP over CRF signaling through CRF2 R in addictive-related neuronal plasticity and behavior...
2018: Frontiers in Endocrinology
Jack C H Ip, Huawei Mu, Qian Chen, Jin Sun, Santiago Ituarte, Horacio Heras, Bert Van Bocxlaer, Monthon Ganmanee, Xin Huang, Jian-Wen Qiu
BACKGROUND: Gastropoda, with approximately 80,000 living species, is the largest class of Mollusca. Among gastropods, apple snails (family Ampullariidae) are globally distributed in tropical and subtropical freshwater ecosystems and many species are ecologically and economically important. Ampullariids exhibit various morphological and physiological adaptations to their respective habitats, which make them ideal candidates for studying adaptation, population divergence, speciation, and larger-scale patterns of diversity, including the biogeography of native and invasive populations...
March 5, 2018: BMC Genomics
Varsha D Badal, Petras J Kundrotas, Ilya A Vakser
BACKGROUND: Structural modeling of protein-protein interactions produces a large number of putative configurations of the protein complexes. Identification of the near-native models among them is a serious challenge. Publicly available results of biomedical research may provide constraints on the binding mode, which can be essential for the docking. Our text-mining (TM) tool, which extracts binding site residues from the PubMed abstracts, was successfully applied to protein docking (Badal et al...
March 5, 2018: BMC Bioinformatics
Uday Sankar Midya, Sanjoy Bandyopadhyay
Ice growth and melting inhibition activities of antifreeze proteins (AFPs) are better explained by adsorption-inhibition mechanism. Inhibition occurs as a result of Kelvin effect induced by adsorbed protein molecules on the surface of seed ice crystal. However, the Kelvin effect has not been explored by the state-of-the-art experimental techniques. In this work, atomistic molecular dynamics simulations have been carried out with Tenebrio molitor antifreeze protein (TmAFP) placed at ice-water interface to probe the Kelvin effect in the mechanism of AFPs...
February 28, 2018: Journal of Physical Chemistry. B
Iddo Vardi, Ortal Barel, Michal Sperber, Michael Schvimer, Moran Nunberg, Michael Field, Jodie Ouahed, Dina Marek-Yagel, Lael Werner, Yael Haberman, Avishay Lahad, Yair Anikster, Gideon Rechavi, Iris Barshack, Joshua J McElwee, Joseph Maranville, Raz Somech, Scott B Snapper, Batia Weiss, Dror S Shouval
BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease. AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis...
February 26, 2018: Digestive Diseases and Sciences
Suvobrata Chakravarty, Adron Robert Ung, Brian G Moore, Jay S Shore, Mona Alshamrani
The edgewise interactions of anions with phenylalanine (Phe) aromatic rings in proteins, known as anion-π interactions, have been well studied. However, the anion-π interactions of the tyrosine (Tyr) and tryptophan (Trp) rings have been less well studied, probably because these have been considered weaker interactions than anions hydrogen bonded to Trp/Tyr sidechains. Distinguishing from such hydrogen bonding interactions, we comprehensively surveyed the edgewise interactions of certain anions (aspartate, glutamate, and phosphate) with Trp, Tyr, and Phe rings in high-resolution, non-redundant protein single chains and interfaces (protein-protein, DNA/RNA-protein, and membrane-protein)...
February 26, 2018: Biochemistry
Clément Viricel, Simon de Givry, Thomas Schiex, Sophie Barbe
Motivation: Accurate and economic methods to predict change in protein binding free energy upon mutation are imperative to accelerate the design of proteins for a wide range of applications. Free energy is defined by enthalpic and entropic contributions. Following the recent progresses of Artificial Intelligence-based algorithms for guaranteed NP-hard energy optimization and partition function computation, it becomes possible to quickly compute minimum energy conformations and to reliably estimate the entropic contribution of side-chains in the change of free energy of large protein interfaces...
February 20, 2018: Bioinformatics
Anna Gogleva, Hajk-Georg Drost, Sebastian Schornack
Motivation: The secretome denotes the collection of secreted proteins exported outside of the cell. The functional roles of secreted proteins include the maintenance and remodelling of the extracellular matrix as well as signalling between host and non-host cells. These features make secretomes rich reservoirs of biomarkers for disease classification and host-pathogen interaction studies. Common biomarkers are extracellular proteins secreted via classical pathways that can be predicted from sequence by annotating the presence or absence of N-terminal signal peptides...
February 16, 2018: Bioinformatics
Anssi Nurminen, Vesa P Hytönen, Alfonso Valencia
Motivation: StructureMapper is a high-throughput algorithm for automated mapping of protein primary amino sequence locations to existing three-dimensional protein structures. The algorithm is intended for facilitating easy and efficient utilization of structural information in protein characterization and proteomics. StructureMapper provides an analysis of the identified structural locations that includes surface accessibility, flexibility, protein-protein interfacing, intrinsic disorder prediction, secondary structure assignment, biological assembly information, and sequence identity percentages, among other metrics...
February 14, 2018: Bioinformatics
Juan M Vanegas, Frank Heinrich, David M Rogers, Bryan D Carson, Sadie La Bauve, Briana C Vernon, Bulent Akgun, Sushil Satija, Aihua Zheng, Margaret Kielian, Susan B Rempe, Michael S Kent
The envelope (E) protein of Dengue virus rearranges to a trimeric hairpin to mediate fusion of the viral and target membranes, which is essential for infectivity. Insertion of E into the target membrane serves to anchor E and possibly also to disrupt local order within the membrane. Both aspects are likely to be affected by the depth of insertion, orientation of the trimer with respect to the membrane normal, and the interactions that form between trimer and membrane. In the present work, we resolved the depth of insertion, the tilt angle, and the fundamental interactions for the soluble portion of Dengue E trimers (sE) associated with planar lipid bilayer membranes of various combinations of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-glycerol (POPG), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), and cholesterol (CHOL) by neutron reflectivity (NR) and by molecular dynamics (MD) simulations...
February 12, 2018: Biochimica et Biophysica Acta
Jasmin Cevost, Cédric Vaillant, Sam Meyer, Burkhard Rost
Motivation: Many DNA-binding proteins recognize their target sequences indirectly, by sensing DNA's response to mechanical distortion. ThreaDNA estimates this response based on high-resolution structures of the protein-DNA complex of interest. Implementing an efficient nanoscale modeling of DNA deformations involving essentially no adjustable parameters, it returns the profile of deformation energy along whole genomes, at base-pair resolution, within minutes on usual laptop/desktop computers...
February 15, 2018: Bioinformatics
Chi-Chou Huang, Chi-Chang Chang, Chi-Wei Chen, Shao-Yu Ho, Hsung-Pin Chang, Yen-Wei Chu
Protein quaternary structure complex is also known as a multimer, which plays an important role in a cell. The dimer structure of transcription factors is involved in gene regulation, but the trimer structure of virus-infection-associated glycoproteins is related to the human immunodeficiency virus. The classification of the protein quaternary structure complex for the post-genome era of proteomics research will be of great help. Classification systems among protein quaternary structures have not been widely developed...
February 14, 2018: Genes
Sebastian Raschka, Alex J Wolf, Joseph Bemister-Buffington, Leslie A Kuhn
Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity...
February 12, 2018: Journal of Computer-aided Molecular Design
J C Gaines, S Acebes, A Virrueta, M Butler, L Regan, C S O'Hern
We compare side chain prediction and packing of core and non-core regions of soluble proteins, protein-protein interfaces, and transmembrane proteins. We first identified or created comparable databases of high-resolution crystal structures of these three protein classes. We show that the solvent-inaccessible cores of the three classes of proteins are equally densely packed. As a result, the side chains of core residues at protein-protein interfaces and in the membrane-exposed regions of transmembrane proteins can be predicted by the hard-sphere plus stereochemical constraint model with the same high prediction accuracies (> 90%) as core residues in soluble proteins...
February 10, 2018: Proteins
T L Leighton, M C Mok, M S Junop, P L Howell, L L Burrows
Pseudomonas aeruginosa uses long, thin fibres called type IV pili (T4P) for adherence to surfaces, biofilm formation, and twitching motility. A conserved subcomplex of PilMNOP is required for extension and retraction of T4P. To better understand its function, we attempted to co-crystallize the soluble periplasmic portions of PilNOP, using reductive surface methylation to promote crystal formation. Only PilOΔ109 crystallized; its structure was determined to 1.7 Å resolution using molecular replacement. This new structure revealed two novel features: a shorter N-terminal α1-helix followed by a longer unstructured loop, and a discontinuous β-strand in the second αββ motif, mirroring that in the first motif...
February 8, 2018: Scientific Reports
Zhe Wang, Yu Kang, Dan Li, Huiyong Sun, Xiaowu Dong, Xiaojun Yao, Lei Xu, Shan Chang, Youyong Li, Tingjun Hou
Protein-protein interactions (PPIs) have been regarded as novel and highly promising drug targets in drug discovery. Numerous new experimental techniques and computational approaches have been developed to assist the design of PPI modulators during the past two decades. However, identification and optimization of small-molecule inhibitors targeting PPIs is still a particularly challenging task due to the 'undruggable' profiles of PPI interfaces. Nowadays, in silico screening, especially docking-based virtual screening (DBVS), has emerged as an effective method to complement experimental high-throughput screening (HTS) in identifying novel and potent small-molecule PPI inhibitors...
February 8, 2018: Journal of Physical Chemistry. B
Yi-Han Lin, María Lucas, Timothy R Evans, Guillermo Abascal-Palacios, Alexandra G Doms, Nicole A Beauchene, Adriana L Rojas, Aitor Hierro, Matthias P Machner
The eukaryotic ubiquitylation machinery catalyzes the covalent attachment of the small protein modifier ubiquitin to cellular target proteins in order to alter their fate. Microbial pathogens exploit this post-translational modification process by encoding molecular mimics of E3 ubiquitin ligases, eukaryotic enzymes that catalyze the final step in the ubiquitylation cascade. Here, we show that the Legionella pneumophila effector protein RavN belongs to a growing class of bacterial proteins that mimic host cell E3 ligases to exploit the ubiquitylation pathway...
February 7, 2018: PLoS Pathogens
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