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https://www.readbyqxmd.com/read/28334219/a-network-model-predicts-the-intensity-of-residue-protein-thermal-coupling
#1
Luciano Censoni, Heloisa Dos Santos Muniz, Leandro Martínez
Motivation: The flow of vibrational energy in proteins has been shown not to obey expectations for isotropic media. The existence of preferential pathways for energy transport, with probable connections to allostery mechanisms, has been repeatedly demonstrated. Here, we investigate whether, by representing a set of protein structures as networks of interacting amino acid residues, we are able to model heat diffusion and predict residue-protein vibrational couplings, as measured by the Anisotropic Thermal Diffusion (ATD) computational protocol of modified molecular dynamics simulations...
March 7, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28321930/uncovering-allostery-and-regulation-in-samhd1-through-molecular-dynamics-simulations
#2
Kajwal Kumar Patra, Akash Bhattacharya, Swati Bhattacharya
The human sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a retroviral restriction factor in myeloid cells and non-cycling CD4+ T cells, a feature imputed to its phosphohydrolase activity - the enzyme depletes the cellular dNTP levels inhibiting reverse transcription. The functionally active form of SAMHD1 is an allosterically triggered tetramer which utilizes GTP-Mg(+2) -dNTP cross bridges to link and stabilize adjacent monomers. However, very little is known about how it assembles into a tetramer and how long the tetramer stays intact...
March 21, 2017: Proteins
https://www.readbyqxmd.com/read/28289188/ligand-induced-allostery-in-the-interaction-of-the-pseudomonas-aeruginosa-heme-binding-protein-with-heme-oxygenase
#3
Daniel J Deredge, Weiliang Huang, Colleen Hui, Hirotoshi Matsumura, Zhi Yue, Pierre Moënne-Loccoz, Jana Shen, Patrick L Wintrode, Angela Wilks
A heme-dependent conformational rearrangement of the C-terminal domain of heme binding protein (PhuS) is required for interaction with the iron-regulated heme oxygenase (HemO). Herein, we further investigate the underlying mechanism of this conformational rearrangement and its implications for heme transfer via site-directed mutagenesis, resonance Raman (RR), hydrogen-deuterium exchange MS (HDX-MS) methods, and molecular dynamics (MD). HDX-MS revealed that the apo-PhuS C-terminal α6/α7/α8-helices are largely unstructured, whereas the apo-PhuS H212R variant showed an increase in structure within these regions...
March 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28282132/quantifying-allosteric-communication-via-both-concerted-structural-changes-and-conformational-disorder-with-cards
#4
Sukrit Singh, Gregory R Bowman
Allosteric (i.e. long-range) communication within proteins is crucial for many biological processes, such as the activation of signaling cascades in response to specific stimuli. However, the physical basis for this communication remains unclear. Existing computational methods for identifying allostery focus on the role of concerted structural changes, but recent experimental work demonstrates that disorder is also an important factor. Here, we introduce the Correlation of All Rotameric and Dynamical States (CARDS) framework for quantifying correlations between both the structure and disorder of different regions of a protein...
March 10, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28275738/long-range-allosteric-signaling-in-red-light-regulated-diguanylyl-cyclases
#5
Geoffrey Gourinchas, Stefan Etzl, Christoph Göbl, Uršula Vide, Tobias Madl, Andreas Winkler
Nature has evolved an astonishingly modular architecture of covalently linked protein domains with diverse functionalities to enable complex cellular networks that are critical for cell survival. The coupling of sensory modules with enzymatic effectors allows direct allosteric regulation of cellular signaling molecules in response to diverse stimuli. We present molecular details of red light-sensing bacteriophytochromes linked to cyclic dimeric guanosine monophosphate-producing diguanylyl cyclases. Elucidation of the first crystal structure of a full-length phytochrome with its enzymatic effector, in combination with the characterization of light-induced changes in conformational dynamics, reveals how allosteric light regulation is fine-tuned by the architecture and composition of the coiled-coil sensor-effector linker and also the central helical spine...
March 2017: Science Advances
https://www.readbyqxmd.com/read/28266924/an-evolution-based-strategy-for-engineering-allosteric-regulation
#6
David Pincus, Orna Resnekov, Kimberly Reynolds
Allosteric regulation provides a way to control protein activity at the time scale of milliseconds to seconds inside the cell. An ability to engineer synthetic allosteric systems would be of practical utility for the development of novel biosensors, creation of synthetic cell signaling pathways, and design of small molecule pharmaceuticals with regulatory impact. To this end, we outline a general approach - termed Rational Engineering of Allostery at Conserved Hotspots (REACH) - to introduce novel regulation into a protein of interest by exploiting latent allostery that has been hard-wired by evolution into its structure...
March 6, 2017: Physical Biology
https://www.readbyqxmd.com/read/28256224/lipid-mediated-regulation-of-embedded-receptor-kinases-via-parallel-allosteric-relays
#7
Madhubrata Ghosh, Loo Chien Wang, Ranita Ramesh, Leslie K Morgan, Linda J Kenney, Ganesh S Anand
Membrane-anchored receptors are essential cellular signaling elements for stimulus sensing, propagation, and transmission inside cells. However, the contributions of lipid interactions to the function and dynamics of embedded receptor kinases have not been described in detail. In this study, we used amide hydrogen/deuterium exchange mass spectrometry, a sensitive biophysical approach, to probe the dynamics of a membrane-embedded receptor kinase, EnvZ, together with functional assays to describe the role of lipids in receptor kinase function...
February 28, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28245055/c-terminal-dimerization-of-apo-cyclic-amp-receptor-protein-validated-in-solution
#8
Dae-Won Sim, Jae-Wan Choi, Ji-Hun Kim, Kyoung-Seok Ryu, Myeongkyu Kim, Hee-Wan Yu, Ku-Sung Jo, Eun-Hee Kim, Min-Duk Seo, Young-Ho Jeon, Bong-Jin Lee, Young Pil Kim, Hyung-Sik Won
Although cyclic AMP receptor protein (CRP) has long served as a typical example of effector-mediated protein allostery, mechanistic details into its regulation have been controversial due to discrepancy between the known crystal structure and NMR structure of apo-CRP. Here, we report that the recombinant protein corresponding to its C-terminal DNA-binding domain (CDD) forms a dimer. This result, together with structural information obtained in the present NMR study, is consistent with the previous crystal structure and validates its relevance also in solution...
February 28, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28240893/how-intrinsic-dynamics-mediate-the-allosteric-mechanism-in-the-abc-transporter-nucleotide-binding-domain-dimer
#9
Peter M Jones, Anthony M George
A protein's architecture facilitates specific motions - intrinsic dynamic modes - that are employed to effect function. Here we used molecular dynamics (MD) simulations to investigate the dynamics of the MJ0796 ABC transporter nucleotide-binding domain (NBD). ABC transporter NBDs form a rotationally symmetric dimer whereby two equivalent active sites are formed at their interface; in complex with a dimer of transmembrane domains they hydrolyse ATP to energise translocation of substrates across cellular membranes...
February 27, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28223534/designing-allostery-inspired-response-in-mechanical-networks
#10
Jason W Rocks, Nidhi Pashine, Irmgard Bischofberger, Carl P Goodrich, Andrea J Liu, Sidney R Nagel
Recent advances in designing metamaterials have demonstrated that global mechanical properties of disordered spring networks can be tuned by selectively modifying only a small subset of bonds. Here, using a computationally efficient approach, we extend this idea to tune more general properties of networks. With nearly complete success, we are able to produce a strain between any two target nodes in a network in response to an applied source strain on any other pair of nodes by removing only ∼1% of the bonds...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28218303/a-combination-of-mutational-and-computational-scanning-guides-the-design-of-an-artificial-ligand-binding-controlled-lipase
#11
Marco Kaschner, Oliver Schillinger, Timo Fettweiss, Christina Nutschel, Frank Krause, Alexander Fulton, Birgit Strodel, Andreas Stadler, Karl-Erich Jaeger, Ulrich Krauss
Allostery, i.e. the control of enzyme activity by a small molecule at a location distant from the enzyme's active site, represents a mechanism essential for sustaining life. The rational design of allostery is a non-trivial task but can be achieved by fusion of a sensory domain, which responds to environmental stimuli with a change in its structure. Hereby, the site of domain fusion is difficult to predict. We here explore the possibility to rationally engineer allostery into the naturally not allosterically regulated Bacillus subtilis lipase A, by fusion of the citrate-binding sensor-domain of the CitA sensory-kinase of Klebsiella pneumoniae...
February 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28212750/conformational-rigidity-and-protein-dynamics-at-distinct-timescales-regulate-ptp1b-activity-and-allostery
#12
Meng S Choy, Yang Li, Luciana E S F Machado, Micha B A Kunze, Christopher R Connors, Xingyu Wei, Kresten Lindorff-Larsen, Rebecca Page, Wolfgang Peti
Protein function originates from a cooperation of structural rigidity, dynamics at different timescales, and allostery. However, how these three pillars of protein function are integrated is still only poorly understood. Here we show how these pillars are connected in Protein Tyrosine Phosphatase 1B (PTP1B), a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways. By combining new experimental and computational data on WT-PTP1B and ≥10 PTP1B variants in multiple states, we discovered a fundamental and evolutionarily conserved CH/π switch that is critical for positioning the catalytically important WPD loop...
February 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28200021/statistical-database-analysis-of-the-role-of-loop-dynamics-for-protein-protein-complex-formation-and-allostery
#13
Yina Gu, Da-Wei Li, Rafael Brüschweiler
No abstract text is available yet for this article.
February 13, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28190781/predicting-protein-dynamics-and-allostery-using-multi-protein-atomic-distance-constraints
#14
Joe G Greener, Ioannis Filippis, Michael J E Sternberg
The related concepts of protein dynamics, conformational ensembles and allostery are often difficult to study with molecular dynamics (MD) due to the timescales involved. We present ExProSE (Exploration of Protein Structural Ensembles), a distance geometry-based method that generates an ensemble of protein structures from two input structures. ExProSE provides a unified framework for the exploration of protein structure and dynamics in a fast and accessible way. Using a dataset of apo/holo pairs it is shown that existing coarse-grained methods often cannot span large conformational changes...
March 7, 2017: Structure
https://www.readbyqxmd.com/read/28188293/asymmetric-configurations-in-a-reengineered-homodimer-reveal-multiple-subunit-communication-pathways-in-protein-allostery
#15
Maria Fe Lanfranco, Fernanda Gárate, Ashton J Engdahl, Rodrigo A Maillard
Many allosteric proteins form homo-oligomeric complexes to regulate a biological function. In homo-oligomers, subunits establish communication pathways that are modulated by external stimuli like ligand binding. A challenge for dissecting the communication mechanisms in homo-oligomers is identifying intermediate liganded states, which are typically transiently populated. However, their identities provide the most mechanistic information on how ligand-induced signals propagate from bound to empty subunits. Here, we dissected the directionality and magnitude of subunit communication in a reengineered, single-chain version of the homodimeric transcription factor cAMP Receptor Protein (CRPSC)...
February 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28166054/elucidation-of-a-four-site-allosteric-network-in-fibroblast-growth-factor-receptor-tyrosine-kinases
#16
Huaibin Chen, William M Marsiglia, Min-Kyu Cho, Zhifeng Huang, Jingjing Deng, Steven P Blais, Weiming Gai, Shibani Bhattacharya, Thomas A Neubert, Nathaniel J Traaseth, Moosa Mohammadi
Receptor tyrosine kinase (RTK) signaling is tightly regulated by protein allostery within the intracellular tyrosine kinase domains. Yet the molecular determinants of allosteric connectivity in tyrosine kinase domain are incompletely understood. By means of structural (X-ray and NMR) and functional characterization of pathogenic gain-of-function mutations affecting the FGF receptor (FGFR) tyrosine kinase domain, we elucidated a long-distance allosteric network composed of four interconnected sites termed the 'molecular brake', 'DFG latch', 'A-loop plug', and 'αC tether'...
February 6, 2017: ELife
https://www.readbyqxmd.com/read/28135092/evolutionary-covariance-combined-with-molecular-dynamics-predicts-a-framework-for-allostery-in-the-muts-dna-mismatch-repair-protein
#17
Bharat Lakhani, Kelly M Thayer, Manju M Hingorani, David L Beveridge
Mismatch repair (MMR) is an essential, evolutionarily conserved pathway that maintains genome stability by correcting base-pairing errors in DNA. Here we examine the sequence and structure of MutS MMR protein to decipher the amino acid framework underlying its two key activities-recognizing mismatches in DNA and using ATP to initiate repair. Statistical coupling analysis (SCA) identified a network (sector) of coevolved amino acids in the MutS protein family. The potential functional significance of this SCA sector was assessed by performing molecular dynamics (MD) simulations for alanine mutants of the top 5% of 160 residues in the distribution, and control nonsector residues...
March 9, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28134524/monod-wyman-changeux-analysis-of-ligand-gated-ion-channel-mutants
#18
Tal Einav, Rob Phillips
We present a framework for computing the gating properties of ligand-gated ion channel mutants using the Monod-Wyman-Changeux (MWC) model of allostery. We derive simple analytic formulas for key functional properties such as the leakiness, dynamic range, half-maximal effective concentration ([EC50]), and effective Hill coefficient, and explore the full spectrum of phenotypes that are accessible through mutations. Specifically, we consider mutations in the channel pore of nicotinic acetylcholine receptor (nAChR) and the ligand binding domain of a cyclic nucleotide-gated (CNG) ion channel, demonstrating how each mutation can be characterized as only affecting a subset of the biophysical parameters...
February 21, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28126820/experimental-measurement-of-binding-energy-selectivity-and-allostery-using-fluctuation-theorems
#19
Joan Camunas-Soler, Anna Alemany, Felix Ritort
Thermodynamic bulk measurements of binding reactions rely on the validity of the law of mass action and the assumption of a dilute solution. Yet, important biological systems such as allosteric ligand-receptor binding, macromolecular crowding, or misfolded molecules may not follow these assumptions and may require a particular reaction model. Here we introduce a fluctuation theorem for ligand binding and an experimental approach using single-molecule force spectroscopy to determine binding energies, selectivity, and allostery of nucleic acids and peptides in a model-independent fashion...
January 27, 2017: Science
https://www.readbyqxmd.com/read/28098152/human-farnesyl-pyrophosphate-synthase-is-allosterically-inhibited-by-its-own-product
#20
Jaeok Park, Michal Zielinski, Alexandr Magder, Youla S Tsantrizos, Albert M Berghuis
Farnesyl pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target. Recent research has focused around a newly identified druggable pocket near the enzyme's active site. Pharmacological exploitation of this pocket is deemed promising; however, its natural biological function, if any, is yet unknown. Here we report that the product of FPPS, farnesyl pyrophosphate (FPP), can bind to this pocket and lock the enzyme in an inactive state. The Kd for this binding is 5-6 μM, within a catalytically relevant range...
January 18, 2017: Nature Communications
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