Read by QxMD icon Read


Davide Moiani, Daryl A Ronato, Chris A Brosey, Andrew S Arvai, Aleem Syed, Jean-Yves Masson, Elena Petricci, John A Tainer
For inhibitor design, as in most research, the best system is question dependent. We suggest structurally defined allostery to design specific inhibitors that target regions beyond active sites. We choose systems allowing efficient quality structures with conformational changes as optimal for structure-based design to optimize inhibitors. We maintain that evolutionarily related targets logically provide molecular avatars, where this Sanskrit term for descent includes ideas of functional relationships and of being a physical embodiment of the target's essential features without requiring high sequence identity...
2018: Methods in Enzymology
John W Patrick, Christopher D Boone, Wen Liu, Gloria M Conover, Yang Liu, Xiao Cong, Arthur Laganowsky
Membrane proteins interact with a myriad of lipid species in the biological membrane, leading to a bewildering number of possible protein-lipid assemblies. Despite this inherent complexity, the identification of specific protein-lipid interactions and the crucial role of lipids in the folding, structure, and function of membrane proteins is emerging from an increasing number of reports. Fundamental questions remain, however, regarding the ability of specific lipid binding events to membrane proteins to alter remote binding sites for lipids of a different type, a property referred to as allostery [Monod J, Wyman J, Changeux JP (1965) J Mol Biol 12:88-118]...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Yifei Fan, Penelope J Cross, Geoffrey B Jameson, Emily J Parker
Most proteins comprise two or more domains from a limited suite of protein families. These domains are often rearranged in various combinations through gene fusion events to evolve new protein functions, including the acquisition of protein allostery through the incorporation of regulatory domains. The enzyme 3-deoxy-d- arabino -heptulosonate 7-phosphate synthase (DAH7PS) is the first enzyme of aromatic amino acid biosynthesis and displays a diverse range of allosteric mechanisms. DAH7PSs adopt a common architecture with a shared (β/α)8 catalytic domain which can be attached to an ACT-like or a chorismate mutase regulatory domain that operates via distinct mechanisms...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Qiang Yan, Miaomiao Xu, Lianxiao Liu
Protein allostery, as a tiny chemical-to-mechanical effect that can precisely regulate protein conformation, exists in many proteins. Here we demonstrate that protein allostery can be used to drive self-assembly for construction of tunable protein architectures. Calmodulin (CaM) is chosen as a model allosteric protein. Folding the CaM conformation can activate the CaM and its ligand to self-assemble into 1D protein helical microfilament. Reversibly, unfolding the CaM can unwind and further dissociate the helical assemblies...
March 2, 2018: Angewandte Chemie
Marie-France Langelier, Levani Zandarashvili, Pedro M Aguiar, Ben E Black, John M Pascal
PARP-1 cleaves NAD+ and transfers the resulting ADP-ribose moiety onto target proteins and onto subsequent polymers of ADP-ribose. An allosteric network connects PARP-1 multi-domain detection of DNA damage to catalytic domain structural changes that relieve catalytic autoinhibition; however, the mechanism of autoinhibition is undefined. Here, we show using the non-hydrolyzable NAD+ analog benzamide adenine dinucleotide (BAD) that PARP-1 autoinhibition results from a selective block on NAD+ binding. Following DNA damage detection, BAD binding to the catalytic domain leads to changes in PARP-1 dynamics at distant DNA-binding surfaces, resulting in increased affinity for DNA damage, and providing direct evidence of reverse allostery...
February 27, 2018: Nature Communications
Marianna Rossetti, Alessandro Porchetta
DNA-based switches are structure-switching biomolecules widely employed in different bioanalytical applications. Of particular interest are DNA-based switches whose activity is regulated through the use of allostery. Allostery is a naturally occurring mechanism in which ligand binding induces the modulation and fine control of a connected biomolecule function as a consequence of changes in concentration of the effector. Through this general mechanism, many different allosteric DNA-based switches able to respond in a highly controlled way at the presence of a specific molecular effector have been engineered...
July 5, 2018: Analytica Chimica Acta
George P Lisi, Allen A Currier, J Patrick Loria
The enzyme imidazole glycerol phosphate synthase (IGPS) is a model for studies of long-range allosteric regulation in enzymes. Binding of the allosteric effector ligand N'-[5'-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide-ribonucleotide (PRFAR) stimulates millisecond (ms) timescale motions in IGPS that enhance its catalytic function. We studied the effect of temperature on these critical conformational motions and the catalytic mechanism of IGPS from the hyperthermophile Thermatoga maritima in an effort to understand temperature-dependent allostery...
2018: Frontiers in Molecular Biosciences
Bryan VanSchouwen, Giuseppe Melacini
Hyperpolarization-activated cyclic-nucleotide-modulated (HCN) ion channels control rhythmicity in neurons and cardiomyocytes. Cyclic AMP (cAMP) modulates HCN activity through the cAMP-induced formation of a tetrameric gating ring spanning the intracellular region (IR) of HCN. Although evidence from confocal patch-clamp fluorometry indicates that the cAMP-dependent gating of HCN occurs through a dimer of dimers, the structural and dynamical basis of cAMP allostery in HCN dimers has so far remained elusive. Thus, here we examine how dimers influence IR structural dynamics, and the role that such structural dynamics play in HCN allostery...
February 20, 2018: Journal of Physical Chemistry. B
Quinlin M Hanson, Jeffrey R Carley, Tyler J Gilbreath, Brian C Smith, Eric S Underbakke
Nitric oxide synthase (NOS) is the primary generator of nitric oxide signals controlling diverse physiological processes such as neurotransmission and vasodilation. NOS activation is contingent on Ca2+ /calmodulin binding at a linker between its oxygenase and reductase domains to induce large conformational changes that orchestrate inter-domain electron transfer. However, the structural dynamics underlying activation of full-length NOS remain ambiguous. Employing hydrogen-deuterium exchange mass spectrometry, we reveal mechanisms underlying neuronal NOS (nNOS) activation by calmodulin and regulation by phosphorylation...
February 16, 2018: Journal of Molecular Biology
Magdalena Korczynska, Mary J Clark, Celine Valant, Jun Xu, Ee Von Moo, Sabine Albold, Dahlia R Weiss, Hayarpi Torosyan, Weijiao Huang, Andrew C Kruse, Brent R Lyda, Lauren T May, Jo-Anne Baltos, Patrick M Sexton, Brian K Kobilka, Arthur Christopoulos, Brian K Shoichet, Roger K Sunahara
Subtype-selective antagonists for muscarinic acetylcholine receptors (mAChRs) have long been elusive, owing to the highly conserved orthosteric binding site. However, allosteric sites of these receptors are less conserved, motivating the search for allosteric ligands that modulate agonists or antagonists to confer subtype selectivity. Accordingly, a 4.6 million-molecule library was docked against the structure of the prototypical M 2 mAChR, seeking molecules that specifically stabilized antagonist binding. This led us to identify a positive allosteric modulator (PAM) that potentiated the antagonist N -methyl scopolamine (NMS)...
February 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Siqi Tian, Wipapat Kladwang, Rhiju Das
The structural interconversions that mediate the gene regulatory functions of RNA molecules may be different from classic models of allostery, but the relevant structural correlations have remained elusive in even intensively studied systems. Here, we present a four-dimensional expansion of chemical mapping called lock-mutate-map-rescue (LM 2 R), which integrates multiple layers of mutation with nucleotide-resolution chemical mapping. This technique resolves the core mechanism of the adenine-responsive V. vulnificus add riboswitch, a paradigmatic system for which both Monod-Wyman-Changeux (MWC) conformational selection models and non-MWC alternatives have been proposed...
February 15, 2018: ELife
Jing Li, Jordan T White, Harry Saavedra, James O Wrabl, Hesam N Motlagh, Kaixian Liu, James Sowers, Trina A Schroer, E Brad Thompson, Vincent J Hilser
No abstract text is available yet for this article.
February 12, 2018: ELife
Jianmin Zhao, Jiaxi Gao, Ting Zheng, Zhehan Yang, Yaqin Chai, Shihong Chen, Ruo Yuan, Wenju Xu
The portable and rapid detection of biomolecules via pH meters to monitor the concentration of hydrogen ions (H+) from biological reactions (e.g. loop-mediated isothermal amplification, LAMP) has attracted research interest. However, this assay strategy suffered from inherent drawback of low sensitivity, resulting in great limitations in practical applications. Herein, a novel electrochemical biosensor was constructed for highly sensitive detection of Nosema bombycis gene DNA (PTP1) through transducing chemical stimuli H+ from PTP1-based LAMP into electrochemical output signal of electroactive ferrocene (Fc)...
February 2, 2018: Biosensors & Bioelectronics
Zijun Li, Jian Zhao, Zhaoyin Wang, Zhihui Dai
Since abnormal metabolism of histidine (His) is defined as an indicator of several diseases, detection of His in biological fluids becomes increasingly urgent to us. However, due to similar structures and properties of different amino acids, selective quantification of His is difficulty, and typically needs the participation of special reagents. In this work, we report for the first time that nickel ions (Ni2+) can induce the allostery of G-quadruplex, and is thus able to manipulate the activity of G-quadruplex DNAzyme...
May 30, 2018: Analytica Chimica Acta
Jarjapu Mahita, Ramanathan Sowdhamini
Extensive research performed on Toll-like receptor (TLR) signalling has identified residues in the Toll/interleukin-1 receptor (TIR) domains that are essential for its proper functioning. Among these residues, those in BB loop are particularly significant as single amino acid mutations in this region can cause drastic changes in downstream signalling. However, while the effect of these mutations on the function is well studied (like the P681H mutation in TLR2, the A795P mutation in TLR3, and the P714H mutation in TLR4), their influence on the dynamics and inter-residue networks is not well understood...
January 31, 2018: Proteins
Paul Campitelli, Jingjing Guo, Huan-Xiang Zhou, Sefika Banu Ozkan
Allostery, which is regulation from distant sites, plays a major role in biology. While traditional allostery is described in terms of conformational change upon ligand binding as an underlying principle, it is possible to have allosteric regulations without significant conformational change through modulating the conformational dynamics by altering the local effective elastic modulus of the protein upon ligand binding. Pin1 utilizes this dynamic allostery to regulate its function. It is a modular protein containing a WW domain and a larger peptidyl prolyl isomerase domain (PPIase) that isomerizes phospho-serine/threonine-proline (pS/TP) motifs, The WW domain serves as a docking module, whereas catalysis solely takes place within the PPIase...
January 23, 2018: Journal of Physical Chemistry. B
Kellen K Andrilenas, Vijendra Ramlall, Jesse Kurland, Brandon Leung, Allen G Harbaugh, Trevor Siggers
Transcription factors IRF3, IRF5 and IRF7 (IRF3/5/7) have overlapping, yet distinct, roles in the mammalian response to pathogens. To examine the role that DNA-binding specificity plays in delineating IRF3/5/7-specific gene regulation we used protein-binding microarrays (PBMs) to characterize the DNA binding of IRF3/5/7 homodimers. We identified both common and dimer-specific DNA binding sites, and show that DNA-binding differences can translate into dimer-specific gene regulation. Central to the antiviral response, IRF3/5/7 regulate type I interferon (IFN) genes...
January 18, 2018: Nucleic Acids Research
Noelia Bernardo-Garcia, Kiran V Mahasenan, Maria T Batuecas, Mijoon Lee, Dusan Hesek, Denisa Petráčková, Linda Doubravová, Pavel Branny, Shahriar Mobashery, Juan A Hermoso
Transpeptidases, members of the penicillin-binding protein (PBP) families, catalyze crosslinking of the bacterial cell wall. This transformation is critical for the survival of bacteria and it is the target of inhibition by -lactam antibiotics. We report herein our structural insights into catalysis by the essential PBP2x of Streptococcus pneumoniae by disclosing a total of four X-ray structures, two computational models based on the crystal structures and molecular-dynamics simulations. The X-ray structures are for the apo PBP2x, the enzyme modified covalently in the active site by oxacillin (a penicillin antibiotic), the enzyme modified by oxacillin in the presence of a synthetic tetrasaccharide surrogate for the cell-wall peptidoglycan and a non-covalent complex of cefepime (a cephalosporin antibiotic) bound to the active site...
January 22, 2018: ACS Chemical Biology
Lakshmi Maganti, Sutapa Dutta, Mahua Ghosh, J Chakrabarti
Here we study microscopic mechanism of complex formation between Ca2+ bound -calmodulin (holoCaM) and Orai1 that regulates Ca2+-dependent inactivation process in eukaryotic cells. We compute conformational thermodynamic changes in holoCaM with respect to complex of Orai1 bound to C-terminal domain of holoCaM using histograms of dihedral angles of the proteins over trajectories from molecular dynamics simulations. Our analysis shows that the N-terminal domain residues L4, T5, Q41, N42, T44 and E67 of holoCaM get destabilized and disordered due to Orai1 binding to C-terminal domain of calmodulin affect the N-terminal domain residues...
January 18, 2018: Journal of Biomolecular Structure & Dynamics
Varnavas D Mouchlis, Yuan Chen, J Andrew McCammon, Edward A Dennis
We demonstrate that lipidomics coupled with molecular dynamics reveals unique phospholipase A2 specificity toward membrane phospholipid substrates. We discovered unexpected head-group and acyl-chain specificity for three-major human phospholipases A2. These differences between each enzyme's specificity coupled with molecular dynamicsbased structural and binding studies revealed unique active site and interfacial surface binding moieties for each enzyme that explains the observed specificity at a hitherto inaccessible structural level...
January 17, 2018: Journal of the American Chemical Society
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"