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https://www.readbyqxmd.com/read/29033287/rotamer-libraries-for-the-high-resolution-design-of-%C3%AE-amino-acid-foldamers
#1
Andrew M Watkins, Timothy W Craven, P Douglas Renfrew, Paramjit S Arora, Richard Bonneau
β-Amino acids offer attractive opportunities to develop biologically active peptidomimetics, either employed alone or in conjunction with natural α-amino acids. Owing to their potential for unique conformational preferences that deviate considerably from α-peptide geometries, β-amino acids greatly expand the possible chemistries and physical properties available to polyamide foldamers. Complete in silico support for designing new molecules incorporating non-natural amino acids typically requires representing their side-chain conformations as sets of discrete rotamers for model refinement and sequence optimization...
October 12, 2017: Structure
https://www.readbyqxmd.com/read/29033289/foldability-of-a-natural-de-novo-evolved-protein
#2
Dixie Bungard, Jacob S Copple, Jing Yan, Jimmy J Chhun, Vlad K Kumirov, Scott G Foy, Joanna Masel, Vicki H Wysocki, Matthew H J Cordes
The de novo evolution of protein-coding genes from noncoding DNA is emerging as a source of molecular innovation in biology. Studies of random sequence libraries, however, suggest that young de novo proteins will not fold into compact, specific structures typical of native globular proteins. Here we show that Bsc4, a functional, natural de novo protein encoded by a gene that evolved recently from noncoding DNA in the yeast S. cerevisiae, folds to a partially specific three-dimensional structure. Bsc4 forms soluble, compact oligomers with high β sheet content and a hydrophobic core, and undergoes cooperative, reversible denaturation...
October 7, 2017: Structure
https://www.readbyqxmd.com/read/29033288/the-therapeutic-antibody-lm609-selectively-inhibits-ligand-binding-to-human-%C3%AE-v%C3%AE-3-integrin-via-steric-hindrance
#3
Andrew J Borst, Zachary M James, William N Zagotta, Mark Ginsberg, Felix A Rey, Frank DiMaio, Marija Backovic, David Veesler
The LM609 antibody specifically recognizes αVβ3 integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II clinical trials for the treatment of several cancers and was also used for αVβ3-targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of αVβ3 integrin, we solved the structure of the LM609 antigen-binding fragment by X-ray crystallography and determined its binding affinity for αVβ3...
October 7, 2017: Structure
https://www.readbyqxmd.com/read/29033286/botulinum-toxins-a-and-e-inflict-dynamic-destabilization-on-t-snare-to-impair-snare-assembly-and-membrane-fusion
#4
Ryan Khounlo, Jaewook Kim, Linxiang Yin, Yeon-Kyun Shin
Botulinum toxins (BoNTs) A and E block neurotransmitter release by specifically cleaving the C- terminal ends of SNAP-25, a plasma membrane SNARE protein. Here, we find that SNAP-25A and E, the cleavage products of BoNT A and E, respectively, terminate membrane fusion via completely different mechanisms. Combined studies of single-molecule FRET and single-vesicle fusion assays reveal that SNAP-25E is incapable of supporting SNARE pairing and thus, vesicle docking. In contrast, SNAP-25A facilitates robust SNARE pairing and vesicle docking with somewhat reduced SNARE zippering, which leads to severe impairment of fusion pore opening...
October 4, 2017: Structure
https://www.readbyqxmd.com/read/28988748/structural-and-functional-implications-of-human-transforming-growth-factor-%C3%AE-induced-protein-tgfbip-in-corneal-dystrophies
#5
Raquel García-Castellanos, Nadia Sukusu Nielsen, Kasper Runager, Ida B Thøgersen, Marie V Lukassen, Ebbe T Poulsen, Theodoros Goulas, Jan J Enghild, F Xavier Gomis-Rüth
A major cause of visual impairment, corneal dystrophies result from accumulation of protein deposits in the cornea. One of the proteins involved is transforming growth factor β-induced protein (TGFBIp), an extracellular matrix component that interacts with integrins but also produces corneal deposits when mutated. Human TGFBIp is a multi-domain 683-residue protein, which contains one CROPT domain and four FAS1 domains. Its structure spans ∼120 Å and reveals that vicinal domains FAS1-1/FAS1-2 and FAS1-3/FAS1-4 tightly interact in an equivalent manner...
September 27, 2017: Structure
https://www.readbyqxmd.com/read/28988747/structural-insights-into-vlr-fine-specificity-for-blood-group-carbohydrates
#6
Bernard C Collins, Robin J Gunn, Tanya R McKitrick, Richard D Cummings, Max D Cooper, Brantley R Herrin, Ian A Wilson
High-quality reagents to study and detect glycans with high specificity for research and clinical applications are severely lacking. Here, we structurally and functionally characterize several variable lymphocyte receptor (VLR)-based antibodies from lampreys immunized with O erythrocytes that specifically recognize the blood group H-trisaccharide type II antigen. Glycan microarray analysis and biophysical data reveal that these VLRs exhibit greater specificity for H-trisaccharide compared with the plant lectin UEA-1, which is widely used in blood typing...
September 27, 2017: Structure
https://www.readbyqxmd.com/read/28966016/enhancing-structure-prediction-and-design-of-soluble-and-membrane-proteins-with-explicit-solvent-protein-interactions
#7
Jason K Lai, Joaquin Ambia, Yumeng Wang, Patrick Barth
Solvent molecules interact intimately with proteins and can profoundly regulate their structure and function. However, accurately and efficiently modeling protein solvation effects at the molecular level has been challenging. Here, we present a method that improves the atomic-level modeling of soluble and membrane protein structures and binding by efficiently predicting de novo protein-solvent molecule interactions. The method predicted with unprecedented accuracy buried water molecule positions, solvated protein conformations, and challenging mutational effects on protein binding...
September 19, 2017: Structure
https://www.readbyqxmd.com/read/28966017/the-structure-of-the-zmynd8-drebrin-complex-suggests-a-cytoplasmic-sequestering-mechanism-of-zmynd8-by-drebrin
#8
Ningning Yao, Jianchao Li, Haiyang Liu, Jun Wan, Wei Liu, Mingjie Zhang
Malfunctions of the actin binding protein Drebrin have been implicated in various human diseases such as Alzheimer's disease, cognitive impairments, cancer, and digestive disorders, though with poorly understood mechanisms. The ADF-H domain of Drebrin does not contain actin binding and depolymerizing activity. Instead, it binds to a histone marker reader, ZMYND8. Here we present the high-resolution crystal structure of Drebrin ADF-H in complex with the ZMYND8 PHD-BROMO-PWWP tandem, elucidating the mechanistic basis governing the highly specific interaction of the two proteins...
September 13, 2017: Structure
https://www.readbyqxmd.com/read/28943336/the-origins-of-specificity-in-the-microcin-processing-protease-tldd-e
#9
Dmitry Ghilarov, Marina Serebryakova, Clare E M Stevenson, Stephen J Hearnshaw, Dmitry Volkov, Anthony Maxwell, David M Lawson, Konstantin Severinov
TldD and TldE proteins are involved in the biosynthesis of microcin B17 (MccB17), an Escherichia coli thiazole/oxazole-modified peptide toxin targeting DNA gyrase. Using a combination of biochemical and crystallographic methods we show that E. coli TldD and TldE interact to form a heterodimeric metalloprotease. TldD/E cleaves the N-terminal leader sequence from the modified MccB17 precursor peptide, to yield mature antibiotic, while it has no effect on the unmodified peptide. Both proteins are essential for the activity; however, only the TldD subunit forms a novel metal-containing active site within the hollow core of the heterodimer...
September 11, 2017: Structure
https://www.readbyqxmd.com/read/28966018/accommodating-protein-dynamics-in-the-modeling-of-chemical-crosslinks
#10
Matteo T Degiacomi, Carla Schmidt, Andrew J Baldwin, Justin L P Benesch
Chemical crosslinking can identify the neighborhood relationships between specific amino-acid residues in proteins. The interpretation of crosslinking data is typically performed using single, static atomic structures. However, proteins are dynamic, undergoing motions spanning from local fluctuations of individual residues to global motions of protein assemblies. Here we demonstrate that failure to explicitly accommodate dynamics when interpreting crosslinks structurally can lead to considerable errors. We present a method and associated software, DynamXL, which is able to account directly for flexibility in the context of crosslinking modeling...
September 9, 2017: Structure
https://www.readbyqxmd.com/read/28943337/near-atomic-resolution-structure-determination-in-over-focus-with-volta-phase-plate-by-cs-corrected-cryo-em
#11
Xiao Fan, Lingyun Zhao, Chuan Liu, Jin-Can Zhang, Kelong Fan, Xiyun Yan, Hai-Lin Peng, Jianlin Lei, Hong-Wei Wang
Volta phase plate (VPP) is a recently developed transmission electron microscope (TEM) apparatus that can significantly enhance the image contrast of biological samples in cryoelectron microscopy, and therefore provide the possibility to solve structures of relatively small macromolecules at high-resolution. In this work, we performed theoretical analysis and found that using phase plate on objective lens spherical aberration (Cs)-corrected TEM may gain some interesting optical properties, including the over-focus imaging of macromolecules...
September 8, 2017: Structure
https://www.readbyqxmd.com/read/28966015/structural-characterization-of-whirlin-reveals-an-unexpected-and-dynamic-supramodule-conformation-of-its-pdz-tandem
#12
Florent Delhommel, Florence Cordier, Benjamin Bardiaux, Guillaume Bouvier, Baptiste Colcombet-Cazenave, Sébastien Brier, Bertrand Raynal, Sylvie Nouaille, Amel Bahloul, Julia Chamot-Rooke, Michael Nilges, Christine Petit, Nicolas Wolff
Hearing relies on the transduction of sound-evoked vibrations into electric signals, occurring in the stereocilia bundle of hair cells. The bundle is organized in a staircase pattern formed by rows of packed stereocilia. This architecture is pivotal to transduction and involves a network of scaffolding proteins with hitherto uncharacterized features. Key interactions in this network are mediated by PDZ domains. Here, we describe the architecture of the first two PDZ domains of whirlin, a protein involved in these assemblies and associated with congenital deaf-blindness...
September 6, 2017: Structure
https://www.readbyqxmd.com/read/28943338/structure-of-a-reptilian-adenovirus-reveals-a-phage-tailspike-fold-stabilizing-a-vertebrate-virus-capsid
#13
Rosa Menéndez-Conejero, Thanh H Nguyen, Abhimanyu K Singh, Gabriela N Condezo, Rachel E Marschang, Mark J van Raaij, Carmen San Martín
Although non-human adenoviruses (AdVs) might offer solutions to problems posed by human AdVs as therapeutic vectors, little is known about their basic biology. In particular, there are no structural studies on the complete virion of any AdV with a non-mammalian host. We combine mass spectrometry, cryo-electron microscopy, and protein crystallography to characterize the composition and structure of a snake AdV (SnAdV-1, Atadenovirus genus). SnAdV-1 particles contain the genus-specific proteins LH3, p32k, and LH2, a previously unrecognized structural component...
September 6, 2017: Structure
https://www.readbyqxmd.com/read/28919443/fv-clasp-an-artificially-designed-small-antibody-fragment-with-improved-production-compatibility-stability-and-crystallizability
#14
Takao Arimori, Yu Kitago, Masataka Umitsu, Yuki Fujii, Ryoko Asaki, Keiko Tamura-Kawakami, Junichi Takagi
Antibody fragments are frequently used as a "crystallization chaperone" to aid structural analysis of complex macromolecules that are otherwise crystallization resistant, but conventional fragment formats have not been designed for this particular application. By fusing an anti-parallel coiled-coil structure derived from the SARAH domain of human Mst1 kinase to the variable region of an antibody, we succeeded in creating a novel chimeric antibody fragment of ∼37 kDa, termed "Fv-clasp," which exhibits excellent crystallization compatibility while maintaining the binding ability of the original IgG molecule...
September 6, 2017: Structure
https://www.readbyqxmd.com/read/28919442/structural-and-functional-analysis-of-the-c-terminal-region-of-flig-an-essential-motor-component-of-vibrio-na-driven-flagella
#15
Yohei Miyanoiri, Atsushi Hijikata, Yuuki Nishino, Mizuki Gohara, Yasuhiro Onoue, Seiji Kojima, Chojiro Kojima, Tsuyoshi Shirai, Masatsune Kainosho, Michio Homma
The flagellar motor protein complex consists of rotor and stator proteins. Their interaction generates torque of flagellum, which rotates bidirectionally, clockwise (CW) and counterclockwise. FliG, one of the rotor proteins, consists of three domains: N-terminal (FliGN), middle (FliGM), and C-terminal (FliGC). We have identified point mutations in FliGC from Vibrio alginolyticus, which affect the flagellar motility. To understand the molecular mechanisms, we explored the structural and dynamic properties of FliGC from both wild-type and motility-defective mutants...
September 6, 2017: Structure
https://www.readbyqxmd.com/read/28919440/structural-insight-into-blm-recognition-by-topbp1
#16
Luxin Sun, Yuhao Huang, Ross A Edwards, Sukmin Yang, Andrew N Blackford, Wojciech Niedzwiedz, J N Mark Glover
Topoisomerase IIβ binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5 interacts with Bloom syndrome helicase (BLM) to regulate genome stability through either phospho-Ser304 or phospho-Ser338 of BLM. Here we show that TopBP1 BRCT5 specifically interacts with the BLM region surrounding pSer304, not pSer338. Our crystal structure of TopBP1 BRCT4/5 bound to BLM reveals recognition of pSer304 by a conserved pSer-binding pocket, and interactions between an FVPP motif N-terminal to pSer304 and a hydrophobic groove on BRCT5...
September 1, 2017: Structure
https://www.readbyqxmd.com/read/28890361/comprehensive-analysis-of-the-human-sh3-domain-family-reveals-a-wide-variety-of-non-canonical-specificities
#17
Joan Teyra, Haiming Huang, Shobhit Jain, Xinyu Guan, Aiping Dong, Yanli Liu, Wolfram Tempel, Jinrong Min, Yufeng Tong, Philip M Kim, Gary D Bader, Sachdev S Sidhu
SH3 domains are protein modules that mediate protein-protein interactions in many eukaryotic signal transduction pathways. The majority of SH3 domains studied thus far act by binding to proline-rich sequences in partner proteins, but a growing number of studies have revealed alternative recognition mechanisms. We have comprehensively surveyed the specificity landscape of human SH3 domains in an unbiased manner using peptide-phage display and deep sequencing. Based on ∼70,000 unique binding peptides, we obtained 154 specificity profiles for 115 SH3 domains, which reveal that roughly half of the SH3 domains exhibit non-canonical specificities and collectively recognize a wide variety of peptide motifs, most of which were previously unknown...
August 28, 2017: Structure
https://www.readbyqxmd.com/read/28919439/pih1p-tah1p-puts-a-lid-on-hexameric-aaa-atpases-rvb1-2p
#18
Shaoxiong Tian, Ge Yu, Huan He, Yu Zhao, Peilu Liu, Alan G Marshall, Borries Demeler, Scott M Stagg, Hong Li
The Saccharomyces cerevisiae (Sc) R2TP complex affords an Hsp90-mediated and nucleotide-driven chaperone activity to proteins of small ribonucleoprotein particles (snoRNPs). The current lack of structural information on the ScR2TP complex, however, prevents a mechanistic understanding of this biological process. We characterized the structure of the ScR2TP complex made up of two AAA+ ATPases, Rvb1/2p, and two Hsp90 binding proteins, Tah1p and Pih1p, and its interaction with the snoRNP protein Nop58p by a combination of analytical ultracentrifugation, isothermal titration calorimetry, chemical crosslinking, hydrogen-deuterium exchange, and cryoelectron microscopy methods...
August 24, 2017: Structure
https://www.readbyqxmd.com/read/28890362/microsecond-dynamics-and-network-analysis-of-the-hiv-1-sosip-env-trimer-reveal-collective-behavior-and-conserved-microdomains-of-the-glycan-shield
#19
Thomas Lemmin, Cinque Soto, Jonathan Stuckey, Peter D Kwong
The trimeric HIV-1-envelope (Env) spike is one of the most glycosylated protein complexes known, with roughly half its mass comprising host-derived N-linked glycan. Here we use molecular dynamics to provide insight into its structural dynamics and into how both protomer and glycan movements coordinate to shield the Env protein surface. A 2-μs molecular dynamics simulation of a fully glycosylated atomistic model of the HIV-1 SOSIP Env trimer revealed a spectrum of protomer-scissoring and trimer-opening movements...
August 24, 2017: Structure
https://www.readbyqxmd.com/read/28867614/targeting-prolyl-trna-synthetase-to-accelerate-drug-discovery-against-malaria-leishmaniasis-toxoplasmosis-cryptosporidiosis-and-coccidiosis
#20
Vitul Jain, Manickam Yogavel, Haruhisa Kikuchi, Yoshiteru Oshima, Norimitsu Hariguchi, Makoto Matsumoto, Preeti Goel, Bastien Touquet, Rajiv S Jumani, Fabienne Tacchini-Cottier, Karl Harlos, Christopher D Huston, Mohamed-Ali Hakimi, Amit Sharma
Developing anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill >500,000 humans annually. Their causative parasites Plasmodium, Leishmania, Toxoplasma, Cryptosporidium and Eimeria display high conservation in many housekeeping genes, suggesting that these parasites can be attacked by targeting invariant essential proteins. Here, we describe selective and potent inhibition of prolyl-tRNA synthetases (PRSs) from the above parasites using a series of quinazolinone-scaffold compounds...
August 24, 2017: Structure
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