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Ragul Gowthaman, Brian G Pierce
T cell receptors (TCRs), along with antibodies, are responsible for specific antigen recognition in the adaptive immune response, and millions of unique TCRs are estimated to be present in each individual. Understanding the structural basis of TCR targeting has implications in vaccine design, autoimmunity, as well as T cell therapies for cancer. Given advances in deep sequencing leading to immune repertoire-level TCR sequence data, fast and accurate modeling methods are needed to elucidate shared and unique 3D structural features of these molecules which lead to their antigen targeting and cross-reactivity...
May 22, 2018: Nucleic Acids Research
Przemyslaw Miszta, Pawel Pasznik, Jakub Jakowiecki, Agnieszka Sztyler, Dorota Latek, Slawomir Filipek
Due to the involvement of G protein-coupled receptors (GPCRs) in most of the physiological and pathological processes in humans they have been attracting a lot of attention from pharmaceutical industry as well as from scientific community. Therefore, the need for new, high quality structures of GPCRs is enormous. The updated homology modeling service GPCRM ( meets those expectations by greatly reducing the execution time of submissions (from days to hours/minutes) with nearly the same average quality of obtained models...
May 21, 2018: Nucleic Acids Research
Mehrnoosh Fathi-Roudsari, Nader Maghsoudi, Amirhossein Maghsoudi, Sepideh Niazi, Morvarid Soleiman
Reteplase is a third generation tissue plasminogen activator (tPA) with a modified structure and prolonged half-life in comparison to native tPA. As a non-glycosylated protein, reteplase is expressed in Escherichia coli. Due to presence of several disulfide bonds, high level production of reteplase is complicated and needs extra steps for conversion to biologically active form. Auto-induction represents a method for high-yield growth of bacterial cells and higher expression of recombinant proteins. Here we have tried to optimize the auto-induction procedure for soluble and active expression of reteplase in E...
May 15, 2018: Protein Expression and Purification
Xia Wang, Ruirui Li, Wenchao Cui, Qiang Li, Jianzhuang Yao
It is a grand attraction for contemporary biochemists to computationally design enzymes for novel chemical transformation or improved catalytic efficiency. Rosetta by Baker et al. is no doubt the leading software in the protein design society. Generally, optimization of the transition state (TS) is part of the Rosetta's protocol to enhance the catalytic efficiency of target enzymes, since TS stabilization is the determining factor for catalytic efficiency based on the TS theory (TST). However, it is confusing that optimization of the reactant state (RS) also results in significant improvement of catalytic efficiency in some cases, such as design of gluten hydrolase (Kuma030)...
May 4, 2018: Scientific Reports
Dinara R Usmanova, Natalya S Bogatyreva, Joan Ariño Bernad, Aleksandra A Eremina, Anastasiya A Gorshkova, German M Kanevskiy, Lyubov R Lonishin, Alexander V Meister, Alisa G Yakupova, Fyodor A Kondrashov, Dmitry N Ivankov
Motivation: Computational prediction of the effect of mutations on protein stability is used by researchers in many fields. The utility of the prediction methods is affected by their accuracy and bias. Bias, a systematic shift of the predicted change of stability, has been noted as an issue for several methods, but has not been investigated systematically. Presence of the bias may lead to misleading results especially when exploring the effects of combination of different mutations. Results: Here we use a protocol to measure the bias as a function of the number of introduced mutations...
May 2, 2018: Bioinformatics
Nicholas A Marze, Shourya S Roy Burman, William Sheffler, Jeffrey J Gray
Motivation: Binding-induced conformational changes challenge current computational docking algorithms by exponentially increasing the conformational space to be explored. To restrict this search to relevant space, some computational docking algorithms exploit the inherent flexibility of the protein monomers to simulate conformational selection from pre-generated ensembles. As the ensemble size expands with increased flexibility, these methods struggle with efficiency and high false positive rates...
April 30, 2018: Bioinformatics
Yu Han, Kun Zang, Changshui Liu, Yingjie Li, Qingjun Ma
Siderophore-interacting proteins (SIPs) play an important role in iron acquisition in many bacteria. SIPs release iron from the internalized ferric siderophore complex by reducing ferric iron to ferrous iron, but how the iron is reduced is not well understood. Here, a sip gene was identified in the genome of Vibrio anguillarum 775. To further understand the catalytic mechanism of the protein, the SIP was overexpressed in Escherichia coli Rosetta (DE3) cells, purified and crystallized for X-ray diffraction analysis...
May 1, 2018: Acta Crystallographica. Section F, Structural Biology Communications
Mohsen Pourmousa, Hyun D Song, Yi He, Jay W Heinecke, Jere P Segrest, Richard W Pastor
Understanding the function of high-density lipoprotein (HDL) requires detailed knowledge of the structure of its primary protein, apolipoprotein A-I (APOA1). However, APOA1 flexibility and HDL heterogeneity have confounded decades of efforts to determine high-resolution structures and consistent models. Here, molecular dynamics simulations totaling 30 μs on two nascent HDLs, each with 2 APOA1 and either 160 phospholipids and 24 cholesterols or 200 phospholipids and 20 cholesterols, show that residues 1-21 of the N-terminal domains of APOA1 interact via strong salt bridges...
April 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
Keith Brazendale, Michael W Beets, Alex V Rowlands, Jessica L Chandler, Stuart J Fairclough, Lynne M Boddy, Tim S Olds, Gaynor Parfitt, Robert J Noonan, Samantha J Downs, Dylan P Cliff
The ability to compare published group-level estimates of objectively measured moderate-to-vigorous physical activity (MVPA) across studies continues to increase in difficulty. The objective of this study was to develop conversion equations and demonstrate their utility to compare estimates of MVPA derived from the wrist and hip. Three studies of youth (N = 232, 9-12yrs, 50% boys) concurrently wore a hip-worn ActiGraph and a wrist-worn GENEActiv for 7-days. ActiGraph hip count data were reduced using four established cutpoints...
April 30, 2018: Journal of Sports Sciences
Jared Adolf-Bryfogle, Oleks Kalyuzhniy, Michael Kubitz, Brian D Weitzner, Xiaozhen Hu, Yumiko Adachi, William R Schief, Roland L Dunbrack
A structural-bioinformatics-based computational methodology and framework have been developed for the design of antibodies to targets of interest. RosettaAntibodyDesign (RAbD) samples the diverse sequence, structure, and binding space of an antibody to an antigen in highly customizable protocols for the design of antibodies in a broad range of applications. The program samples antibody sequences and structures by grafting structures from a widely accepted set of the canonical clusters of CDRs (North et al., J...
April 27, 2018: PLoS Computational Biology
Jingxue Wang, Huali Cao, John Z H Zhang, Yifei Qi
Computational protein design has a wide variety of applications. Despite its remarkable success, designing a protein for a given structure and function is still a challenging task. On the other hand, the number of solved protein structures is rapidly increasing while the number of unique protein folds has reached a steady number, suggesting more structural information is being accumulated on each fold. Deep learning neural network is a powerful method to learn such big data set and has shown superior performance in many machine learning fields...
April 20, 2018: Scientific Reports
Sharon Guffy, Frank Teets, Minnie Langlois, Brian Kuhlman
We have developed a set of protocols in the molecular modeling program Rosetta for performing requirement-driven protein design. First, the user specifies a set of structural features that they wish to be present in the designed protein. These requirements can be general, e.g. create a protein with five helices, or they can be very specific and require the correct placement of a set of amino acids to bind a ligand. Next, a large set of protein models are generated that satisfy the design requirements. The models are built using a method we recently introduced into Rosetta, called SEWING, that rapidly assembles novel protein backbones by combining pieces of naturally occurring proteins...
April 16, 2018: Journal of Chemical Information and Modeling
Jack B Maguire, Scott E Boyken, David Baker, Brian Kuhlman
Hydrogen bond networks play a critical role in determining the stability and specificity of biomolecular complexes, and the ability to design such networks is important for engineering novel structures, interactions, and enzymes. One key feature of hydrogen bond networks that makes them difficult to rationally engineer is that they are highly cooperative and are not energetically favorable until the hydrogen bonding potential has been satisfied for all buried polar groups in the network. Existing computational methods for protein design are ill-equipped for creating these highly cooperative networks because they rely on energy functions and sampling strategies that are focused on pairwise interactions...
April 20, 2018: Journal of Chemical Theory and Computation
Krissana Boonpa, Supaluk Tantong, Kamonwan Weerawanich, Pawinee Panpetch, Onanong Pringsulaka, Yodying Yingchutrakul, Sittiruk Roytrakul, Supaart Sirikantaramas
According to an in silico analysis, OsGASR3 (LOC_Os03g55290) from rice (Oryza sativa L.) was predicted to be involved in plant defense mechanisms. A semi-quantitative reverse transcription polymerase chain reaction assay revealed that OsGASR3 is highly expressed in the inflorescences of Thai jasmine rice (O. sativa L. subsp. indica 'KDML 105'). To characterize the biological activity of OsGASR3, we produced an OsGASR3-glutathione S-transferase fusion protein in Escherichia coli Rosetta-gami (DE3) cells for a final purified recombinant OsGASR3 yield of 0...
March 27, 2018: Journal of Plant Physiology
Ingemar André
Determining high-resolution structures of proteins with helical symmetry can be challenging due to limitations in experimental data. In such instances, structure-based protein simulations driven by experimental data can provide a valuable approach for building models of helical assemblies. This chapter describes how the Rosetta macromolecular package can be used to model homomeric protein assemblies with helical symmetry in a range of modeling scenarios including energy refinement, symmetrical docking, comparative modeling, and de novo structure prediction...
2018: Methods in Molecular Biology
Stephanie S Kim, Justin T Seffernick, Steffen Lindert
Although many proteins necessitate well-folded structures to properly instigate their biological functions, a large fraction of functioning proteins contain regions-known as intrinsically disordered protein regions-where stable structures are not likely to form. Notable functional roles of intrinsically disordered proteins are in transcriptional regulation, translation, and cellular signal transduction. Moreover, intrinsically disordered protein regions are highly abundant in many proteins associated with various human diseases, therefore these segments have become attractive drug targets for potential therapeutics...
March 29, 2018: Journal of Physical Chemistry. B
Binhai Ren, Que T La, Bronwyn A O'Brien, Najah T Nassif, Yi Tan, Dario Gerace, Rosetta Martiniello-Wilks, Fraser Torpy, Allison P Dane, Ian E Alexander, Ann M Simpson
BACKGROUND: Gene therapy is one treatment that may ultimately cure Type 1 diabetes. We have previously shown that introduction of furin-cleavable human insulin (INS-FUR) to the livers in several animal models of diabetes has resulted in reversal of diabetes and partial pancreatic transdifferentiation of liver cells. This study assessed if streptozotocin (STZ)-diabetes could be reversed in FRG mice in which chimeric mouse-human livers can be established, and if pancreatic transdifferentiation occurred in the engrafted human hepatocytes...
March 26, 2018: Journal of Gene Medicine
Elisabetta Ricottini, Fabio Mangiacapra, Annunziata Nusca, Rosetta Melfi, Ilaria Cavallari, Marco Miglionico, Paolo Gallo, Paolo Pozzilli, Germano Di Sciascio
No comprehensive data are available on the role of platelet indexes (PI) in the periprocedural risk stratification of patients who underwent percutaneous coronary intervention (PCI). The aim of this study was to investigate the relation of PI to platelet reactivity (PR) and periprocedural myocardial infarction (PMI) in patients receiving PCI. A total of 502 PCI patients had preprocedural measurement of PI and PR, the latter assessed by VerifyNow P2Y12 assay. Study end points were incidence of PMI and high platelet reactivity (HPR) according to tertiles of PI and evaluation of PI in HPR patients...
February 5, 2018: American Journal of Cardiology
Yi Zhao, Marcus J C Long, Yiran Wang, Sheng Zhang, Yimon Aye
Posttranslational modifications (PTMs) are the lingua franca of cellular communication. Most PTMs are enzyme-orchestrated. However, the reemergence of electrophilic drugs has ushered mining of unconventional/non-enzyme-catalyzed electrophile-signaling pathways. Despite the latest impetus toward harnessing kinetically and functionally privileged cysteines for electrophilic drug design, identifying these sensors remains challenging. Herein, we designed "G-REX"-a technique that allows controlled release of reactive electrophiles in vivo...
February 28, 2018: ACS Central Science
Clement Chung, Shital Patel, Rosetta Lee, Lily Fu, Sean Reilly, Tuyet Ho, Jason Lionetti, Michael D George, Pam Taylor
PURPOSE: The development of a computerized prescriber order-entry (CPOE) system for chemotherapy in a multisite safety-net health system and the challenges to its successful implementation are described. SUMMARY: Before CPOE for chemotherapy was first implemented and embedded in the electronic medical record system of Harris Health System (HHS), pharmacy personnel relied on regimen-specific preprinted order sets. However, due to differences in practice styles and workflow logistics, the paper orders across the 3 facilities were mostly site specific, with varying clinical content...
March 15, 2018: American Journal of Health-system Pharmacy: AJHP
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