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Alexander Jarasch, Arne Skerra
The analysis and comparison of large numbers of immunoglobulin (Ig) sequences that arise during an antibody selection campaign can be time-consuming and tedious. Typically, the identification and annotation of framework as well as complementarity-determining regions (CDRs) is based on multiple sequence alignments using standardized numbering schemes, which allow identification of equivalent residues among different family members but often necessitate expert knowledge and manual intervention. Moreover, due to the enormous length variability of some CDRs the benefit of conventional Ig numbering schemes is limited and the calculation of correct sequence alignments can become challenging...
October 22, 2016: Proteins
Hasup Lee, Minkyung Baek, Gyu Rie Lee, Sangwoo Park, Chaok Seok
Many proteins function as homo- or hetero-oligomers; therefore, attempts to understand and regulate protein functions require knowledge of protein oligomer structures. The number of available experimental protein structures is increasing, and oligomer structures can be predicted using the experimental structures of related proteins as templates. However, template-based models may have errors due to sequence differences between the target and template proteins, which can lead to functional differences. Such structural differences may be predicted by loop modeling of local regions or refinement of the overall structure...
October 22, 2016: Proteins
K M Saravanan, S Suvaithenamudhan, S Parthasarathy, S Selvaraj
To adopt a particular fold, a protein requires several interactions between its amino acid residues. The energetic contribution of these residue-residue interactions can be approximated by extracting statistical potentials from known high resolution structures. Several methods based on statistical potentials extracted from unrelated proteins are found to make a better prediction of probability of point mutations. We postulate that the statistical potentials extracted from known structures of similar folds with varying sequence identity can be a powerful tool to examine probability of point mutation...
October 19, 2016: Proteins
Kaleigh Giles, Benjamin Pluvinage, Alisdair B Boraston
The polysaccharide utilization locus in Bacteroides plebeius that confers the ability to catabolize porphyran contains a putative GH50 β-agarase (BACPLE_01683, BpGH50). BpGH50 did not show any clear activity on agarose or on the related algal galactans porphyran and carrageenan. However, the 1.4 Å resolution x-ray crystal structure of BpGH50 confirmed its possession of the core (α/β)8 barrel fold found in GH50 enzymes as well as the structural conservation of the catalytic residues and some substrate binding residues...
October 18, 2016: Proteins
András Szilágyi, Dániel Györffy, Péter Závodszky
In an earlier study, we showed that two-domain segment-swapped proteins can evolve by domain swapping and fusion, resulting in a protein with two linkers connecting its domains. We proposed that a potential evolutionary advantage of this topology may be the restriction of interdomain motions, which may facilitate domain closure by a hinge-like movement, crucial for the function of many enzymes. Here, we test this hypothesis computationally on uroporphyrinogen III synthase, a two-domain segment-swapped enzyme essential in porphyrin metabolism...
October 18, 2016: Proteins
Ivan Anishchenko, Petras J Kundrotas, Ilya A Vakser
Structural characterization of protein-protein interactions is essential for understanding life processes at the molecular level. However, only a fraction of protein interactions have experimentally resolved structures. Thus reliable computational methods for structural modeling of protein interactions (protein docking) are important for generating such structures and understanding the principles of protein recognition. Template-based docking techniques that utilize structural similarity between target protein-protein interaction and co-crystallized protein-protein complexes (templates) are gaining popularity due to generally higher reliability than that of the template-free docking...
October 18, 2016: Proteins
Thom Vreven, Brian G Pierce, Tyler M Borrman, Zhiping Weng
We report the performance of our protein-protein docking pipeline, including the ZDOCK rigid-body docking algorithm, on 19 targets in CAPRI rounds 28-34. Following the docking step, we reranked the ZDOCK predictions using the IRAD scoring function, pruned redundant predictions, performed energy landscape analysis, and utilized our interface prediction approach RCF. In addition, we applied constraints to the search space based on biological information that we culled from the literature, which increased the chance of making a correct prediction...
October 7, 2016: Proteins
Christoffer H Norn, Gideon Lapidoth, Sarel J Fleishman
Current methods for antibody structure prediction rely on sequence homology to known structures. Although this strategy often yields accurate predictions, models can be stereo-chemically strained. Here, we present a fully automated algorithm, called AbPredict, that disregards sequence homology, and instead uses a Monte Carlo search for low-energy conformations built from backbone segments and rigid-body orientations that appear in antibody molecular structures. We find cases where AbPredict selects accurate loop templates with sequence identity as low as 10%, whereas the template of highest sequence identity diverges substantially from the query's conformation...
October 7, 2016: Proteins
Jinchao Yu, Jessica Andreani, Françoise Ochsenbein, Raphaël Guerois
Computational protein-protein docking is of great importance for understanding protein interactions at the structural level. CAPRI (Critical Assessment of PRediction of Interactions) experiments provide the protein docking community with a unique opportunity to blindly test methods based on real-life cases and help accelerate methodology development. For CAPRI rounds 28-35, we used an automatic docking pipeline integrating the coarse-grained co-evolution-based potential InterEvScore. This score was developed to exploit the information contained in the multiple sequence alignments of binding partners and selectively recognize co-evolved interfaces...
October 4, 2016: Proteins
Ivan Anishchenko, Petras J Kundrotas, Ilya A Vakser
Structural characterization of proteins is essential for understanding life processes at the molecular level. However, only a fraction of known proteins have experimentally determined structures. This fraction is even smaller for protein-protein complexes. Thus, structural modeling of protein-protein interactions (docking) primarily has to rely on modeled structures of the individual proteins, which typically are less accurate than the experimentally determined ones. Such "double" modeling is the Grand Challenge of structural reconstruction of the interactome...
October 4, 2016: Proteins
Chiara Pallara, Brian Jiménez-García, Miguel Romero, Iain H Moal, Juan Fernández-Recio
The 6th CAPRI edition included new modelling challenges, such as the prediction of protein-peptide complexes, and the modelling of homo-oligomers and domain-domain interactions as part of the first joint CASP-CAPRI experiment. Other non-standard targets included the prediction of interfacial water positions and the modelling of the interactions between proteins and nucleic acids. We have participated in all proposed targets of this CAPRI edition both as predictors and as scorers, with new protocols to efficiently use our docking and scoring scheme pyDock in a large variety of scenarios...
October 4, 2016: Proteins
Samira Yazdi, Michael Naumann, Matthias Stein
Activation of the transcription factor NF-κB requires degradation of its physiological inhibitor IκBα in order to allow nuclear translocation of NF-kB. NF-κB activity links inflammation and carcinogenesis and makes its signaling pathway an important target for therapeutic intervention. The signal-receiving N-terminal domain (SRD) of the NF-kB inhibitor IκBα harbors the sites of post-translational modifications (Ser32 and 36) directed by the IκB kinase (IKK) complex. The SRD was originally recognized to be highly disordered, but was recently shown to possess stable secondary structural elements...
October 4, 2016: Proteins
Marwa El Houasli, Bernard Maigret, Marie-Dominique Devignes, Anisah W Ghoorah, Sergei Grudinin, David W Ritchie
Many of the modeling targets in the blind CASP-11/CAPRI-30 experiment were protein homo-dimers and homo-tetramers. Here, we perform a retrospective docking-based analysis of the perfectly symmetrical CAPRI Round 30 targets whose crystal structures have been published. Starting from the CASP "stage-2" fold prediction models, we show that using our recently developed "SAM" polar Fourier symmetry docking algorithm combined with NAMD energy minimisation often gives acceptable or better 3D models of the target complexes...
October 4, 2016: Proteins
Jun Wei Li, Shao Ying Xiao, Xiao Xiao Xie, Hui Zhou, Chun Li Pang, Shan Shan Li, Hai Lin Zhang, Diomedes E Logothetis, Yong Zhan, Hai Long An
Kir2.1 (also known as IRK1) plays key roles in regulation of resting membrane potential and cell excitability. To achieve its physiological roles, Kir2.1 performs a series of conformational transition, named as gating. However, the structural basis of gating is still obscure. Here, we combined site-directed mutation, two-electrode voltage clamp with molecular dynamics simulations and determined that H221 regulates the gating process of Kir2.1 by involving a weak interaction network. Our data show that the H221R mutant accelerates the rundown kinetics and decelerates the reactivation kinetics of Kir2...
October 3, 2016: Proteins
Minli Xing, Robin S Simmonds, Russell Timkovich
Zoocin A is a Zn-metallopeptidase secreted by Streptococcus zooepidemicus strain 4881. Its catalytic domain is responsible for cleaving the D-alanyl-L-alanine peptide bond in streptococcal peptidoglycan. The solution NMR structure of the Cys74 to Ala74 mutant of the recombinant catalytic domain (rCAT C74A) has been determined. With a previous structure determination for the recombinant target recognition domain (rTRD), this completes the 3D structure of zoocin A. While the structure of rCAT C74A resembles those of the catalytic domains of lysostaphin and LytM, the substrate binding groove is wider and no tyrosine residue was observed in the active site...
October 3, 2016: Proteins
Yoshitaka Hiruma, Andre Koch, Shreya Dharadhar, Robbie P Joosten, Anastassis Perrakis
Monopolar spindle 1 (Mps1, also known as TTK) is a protein kinase crucial for ensuring that cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules. Incomplete chromosomal attachment leads to abnormal chromosome counts in the daughter cells (aneuploidy), a condition common in many solid cancers. Therefore Mps1 is an established target in cancer therapy. Mps1 kinase inhibitors include reversine (2-(4-morpholinoanilino)-6-cyclohexylaminopurine), a promiscuous compound first recognized as an inhibitor of the Aurora B mitotic kinase...
October 3, 2016: Proteins
Dong Gao, Wang Li
Toll-like receptors (TLRs) recognize common structural patterns in diverse microbial molecules and play central roles in the innate immune response. The structures of extracellular domains and their ligand complexes of several TLRs have been determined by X-ray crystallography. Here, we discuss recent advances on structures and activation mechanisms of TLRs. Despite the differences in interaction areas of ligand with TLRs, the extracellular domains of TLRs all adopt horseshoe-shaped structures and the overall M-shape of the TLR-ligand complexes is strikingly similar...
October 3, 2016: Proteins
Han Wen, Feng Qin, Wenjun Zheng
As a key cellular sensor, the TRPV1 cation channel undergoes a gating transition from a closed state to an open state in response to various physical and chemical stimuli including noxious heat. Despite years of study, the heat activation mechanism of TRPV1 gating remains enigmatic at the molecular level. Toward elucidating the structural and energetic basis of TRPV1 gating, we have performed molecular dynamics (MD) simulations (with cumulative simulation time of 3 μs), starting from the high-resolution closed and open structures of TRPV1 solved by cryo-electron microscopy...
October 3, 2016: Proteins
Caitlin A Kowalsky, Timothy A Whitehead
The comprehensive sequence determinants of cohesin to binding affinity towards type I dockerin from Clostridium thermocellum and Clostridium cellulolyticum was evaluated using deep mutational scanning coupled to yeast surface display. We measured the relative binding affinity to dockerin for 2,970 and 2,778 single point mutants of C.thermocellum and C. cellulolyticum, respectively, representing over 96% of all possible single point mutants. The interface ΔΔG for each variant was reconstructed from sequencing counts and compared with three independent experimental methods...
October 3, 2016: Proteins
Aoife C Fogarty, Raffaello Potestio, Kurt Kremer
In multi-resolution simulations, different system components are simultaneously modelled at different levels of resolution, these being smoothly coupled together. In the case of enzyme systems, computationally expensive atomistic detail is needed in the active site to capture the chemistry of ligand binding. Global properties of the rest of the protein also play an essential role, determining the structure and fluctuations of the binding site; however, these can be modelled on a coarser level. Similarly, in the most computationally efficient scheme only the solvent hydrating the active site requires atomistic detail...
October 3, 2016: Proteins
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