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https://www.readbyqxmd.com/read/29153319/thermodynamic-coupling-function-analysis-of-allosteric-mechanisms-in-the-human-dopamine-transporter
#1
Michael V LeVine, Michel A Cuendet, Asghar M Razavi, George Khelashvili, Harel Weinstein
Allostery plays a crucial role in the mechanism of neurotransmitter-sodium symporters, such as the human dopamine transporter. To investigate the molecular mechanism that couples the transport-associated inward release of the Na(+) ion from the Na2 site to intracellular gating, we applied a combination of the thermodynamic coupling function (TCF) formalism and Markov state model analysis to a 50-μs data set of molecular dynamics trajectories of the human dopamine transporter, in which multiple spontaneous Na(+) release events were observed...
November 15, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/29151219/implementation-of-the-nmr-chemical-shift-covariance-analysis-chesca-a-chemical-biologist-s-approach-to-allostery
#2
Stephen Boulton, Rajeevan Selvaratnam, Rashik Ahmed, Giuseppe Melacini
Mapping allosteric sites is emerging as one of the central challenges in physiology, pathology, and pharmacology. Nuclear Magnetic Resonance (NMR) spectroscopy is ideally suited to map allosteric sites, given its ability to sense at atomic resolution the dynamics underlying allostery. Here, we focus specifically on the NMR CHEmical Shift Covariance Analysis (CHESCA), in which allosteric systems are interrogated through a targeted library of perturbations (e.g., mutations and/or analogs of the allosteric effector ligand)...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29150976/salt-bridge-interactions-within-the-%C3%AE-2-integrin-%C3%AE-7-helix-mediate-force-induced-binding-and-shear-resistance-ability
#3
Xiao Zhang, Linda Li, Ning Li, Xinyu Shu, Lüwen Zhou, Shouqin Lü, Shenbao Chen, Debin Mao, Mian Long
The functional performance of αI domain α7 helix in β2 integrin activation depends on the allostery of the α7 helix, which axially slides down; therefore, it is critical to elucidate what factors regulate the allostery. In this study, we determined that there were two conservative salt bridge interaction pairs that constrain both the upper and bottom ends of the α7 helix. Molecular Dynamics (MD) simulations for three β2 integrin members of LFA-1 (αL β2 ), Mac-1 (αM β2 ) and αx β2 indicated that the magnitude of the salt bridge interaction is related to the stability of the αI domain and the strength of the corresponding force-induced allostery...
November 18, 2017: FEBS Journal
https://www.readbyqxmd.com/read/29146779/erratum-for-the-report-experimental-measurement-of-binding-energy-selectivity-and-allostery-using-fluctuation-theorems-by-j-camunas-soler-a-alemany-f-ritort
#4
(no author information available yet)
No abstract text is available yet for this article.
November 17, 2017: Science
https://www.readbyqxmd.com/read/29139290/decomposing-dynamical-couplings-in-mutated-scfv-antibody-fragments-into-stabilizing-and-destabilizing-effects
#5
Azhagiya Singam Ettayapuram Ramaprasad, Shahid Uddin, Jose Casas-Finet, Donald J Jacobs
Conformational fluctuations within scFv antibodies are characterized by a novel perturbation-response decomposition of molecular dynamics trajectories. Both perturbation and response profiles are stratified into stabilizing and destabilizing conditions. The linker between the VH and VL domains exhibits the dominant dynamical response by being coupled to nearly the entire protein, responding to both stabilizing and destabilizing perturbations. Perturbations within complementarity-determining regions (CDR) induce rich behavior in dynamic response...
November 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29124793/evidence-for-allosteric-effects-on-p53-oligomerization-induced-by-phosphorylation
#6
Petr Muller, Juliana M Chan, Oliver Simoncik, Miroslav Fojta, David P Lane, Ted Hupp, Borivoj Vojtesek
P53 is a tetrameric protein with a thermodynamically unstable DNA-binding domain flanked by intrinsically disordered regulatory domains that control its activity. The unstable and disordered segments of p53 allow high flexibility as it interacts with binding partners and permits a rapid on/off switch to control its function. The p53 tetramer can exist in multiple conformational states, any of which can be stabilized by a particular modification. Here, we apply the allostery model to p53 to ask whether evidence can be found that the "activating" C-terminal phosphorylation of p53 stabilizes a specific conformation of the protein in the absence of DNA...
November 10, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/29116053/elastic-strain-and-twist-analysis-of-protein-structural-data-and-allostery-of-the-transmembrane-channel-kcsa
#7
Michael Robert Mitchell, Stanislas Leibler
The abundance of available protein static structural data makes more effective analysis and interpretation of this data a valuable tool to supplement experimental study of protein mechanics. Structural displacements can be difficult to analyze and interpret. Previously, we showed that strains provide a more natural and interpretable representation of protein deformations, revealing mechanical coupling between spatially distinct sites of allosteric proteins. Here, we demonstrate that other transformations of displacements yield additional insights...
November 8, 2017: Physical Biology
https://www.readbyqxmd.com/read/29112408/ensemble-and-rigidity-theory-based-perturbation-approach-to-analyze-dynamic-allostery
#8
Christopher Pfleger, Alexander Minges, Markus Boehm, Christopher L McClendon, Rubben Torella, Holger Gohlke
Allostery describes the functional coupling between sites in biomolecules. Recently, the role of changes in protein dynamics for allosteric communication has been highlighted. A quantitative and predictive description of allostery is fundamental for understanding biological processes. Here, we integrate an ensemble-based perturbation approach with the analysis of biomolecular rigidity and flexibility to construct a model of dynamic allostery. Our model by definition excludes the possibility of conformational changes, evaluates static, not dynamic, properties of molecular systems, and describes allosteric effects due to ligand binding in terms of a novel free energy measure...
November 7, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/29106449/allosigma-allosteric-signaling-and-mutation-analysis-server
#9
Enrico Guarnera, Zhen Wah Tan, Zejun Zheng, Igor N Berezovsky
Motivation: Allostery is an omnipresent mechanism of the function modulation in proteins via either effector binding or mutations in the exosites. Despite the growing number of online servers and databases devoted to prediction/classification of allosteric sites and their characteristics, there is a lack of resources for an efficient and quick estimation of the causality and energetics of allosteric communication. Results: The AlloSigMA server implements a unique approach on the basis of the recently introduced structure-based statistical mechanical models of allosteric signaling...
July 6, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29080700/allosteric-pathways-in-nuclear-receptors-potential-targets-for-drug-design
#10
REVIEW
Elias J Fernandez
The nuclear receptor family of transcription factor proteins mediate endocrine function and play critical roles in development, physiology and pharmacology. Malfunctioning nuclear receptors are associated with several disease states. The functional activity of nuclear receptors is regulated by small molecular hormonal and synthetic molecules. Multiple sources of evidence have identified and distinguished between the different allosteric pathways initiated by ligands, DNA and cofactors such as co-activators and co-repressors...
October 25, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29080471/structure-based-prediction-of-protein-allostery
#11
REVIEW
Joe G Greener, Michael Je Sternberg
Allostery is the functional change at one site on a protein caused by a change at a distant site. In order for the benefits of allostery to be taken advantage of, both for basic understanding of proteins and to develop new classes of drugs, the structure-based prediction of allosteric binding sites, modulators and communication pathways is necessary. Here we review the recently emerging field of allosteric prediction, focusing mainly on computational methods. We also describe the search for cryptic binding pockets and attempts to design allostery into proteins...
October 25, 2017: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/29066623/reconciling-contradictory-findings-glucose-transporter-1-glut1-functions-as-an-oligomer-of-allosteric-alternating-access-transporters
#12
Kenneth P Lloyd, Ogooluwa A Ojelabi, Julie K De Zutter, Anthony Carruthers
Recent structural studies suggest that glucose transporter 1 (GLUT1)-mediated sugar transport is mediated by an alternating access transporter that successively presents exofacial (e2) and endofacial (e1) substrate-binding sites. Transport studies, however, indicate multiple, interacting (allosteric), and co-existent, exo- and endofacial GLUT1 ligand-binding sites. The present study asks whether these contradictory conclusions result from systematic analytical error or reveal a more fundamental relationship between transporter structure and function...
October 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29064369/allosteric-fine-tuning-of-the-conformational-equilibrium-poises-the-chaperone-bip-for-post-translational-regulation
#13
Lukasz Wieteska, Saeid Shahidi, Anastasia Zhuravleva
BiP is the only Hsp70 chaperone in the endoplasmic reticulum (ER) and similar to other Hsp70s, its activity relies on nucleotide- and substrate-controllable docking and undocking of its nucleotide-binding domain (NBD) and substrate-binding domain (SBD). However, little is known of specific features of the BiP conformational landscape that tune BiP to its unique tasks and the ER environment. We present methyl NMR analysis of the BiP chaperone cycle that reveals surprising conformational heterogeneity of ATP-bound BiP that distinguishes BiP from its bacterial homologue DnaK...
October 24, 2017: ELife
https://www.readbyqxmd.com/read/29062895/norovirus-escape-from-broadly-neutralizing-antibodies-is-limited-to-allostery-like-mechanisms
#14
Abimbola O Kolawole, Hong Q Smith, Sophia A Svoboda, Madeline S Lewis, Michael B Sherman, Gillian C Lynch, B Montgomery Pettitt, Thomas J Smith, Christiane E Wobus
Ideal antiviral vaccines elicit antibodies (Abs) with broad strain recognition that bind to regions that are difficult to mutate for escape. Using 10 murine norovirus (MNV) strains and 5 human norovirus (HuNoV) virus-like particles (VLPs), we identified monoclonal antibody (MAb) 2D3, which broadly neutralized all MNV strains tested. Importantly, escape mutants corresponding to this antibody were very slow to develop and were distal to those raised against our previously studied antibody, A6.2. To understand the atomic details of 2D3 neutralization, we determined the cryo-electron microscopy (cryo-EM) structure of the 2D3/MNV1 complex...
September 2017: MSphere
https://www.readbyqxmd.com/read/29058683/cooperative-mechanosensitivity-and-allostery-of-focal-adhesion-clusters
#15
Darryl C W Foo, Eugene Terentjev
We analyse a role of cooperative interaction between neighbouring adhesion-mechanosensor complexes by constructing an Ising-like Hamiltonian describing the free energy of cell adhesion on a substrate as a lattice of 3-state mechanosensing sites involving focal adhesion kinase (FAK). We use Monte Carlo stochastic algorithm to find equilibrium configurations of these mechanosensors in two representative geometries: on a 1D ring representing the rim of a cell on flat surface, and a 2D bounded surface representing the whole area of cell contact with flat surface...
October 23, 2017: Physical Biology
https://www.readbyqxmd.com/read/29022880/genetically-tunable-frustration-controls-allostery-in-an-intrinsically-disordered-transcription-factor
#16
Jing Li, Jordan T White, Harry Saavedra, James O Wrabl, Hesam N Motlagh, Kaixian Liu, James Sowers, Trina Schroer, E Brad Thompson, Vincent J Hilser
Intrinsically disordered proteins (IDPs) present a functional paradox because they lack stable tertiary structure, but nonetheless play a central role in signaling, utilizing a process known as allostery. Historically, allostery in structured proteins has been interpreted in terms of propagated structural changes that are induced by effector binding. Thus, it is not clear how IDPs, lacking such well-defined structures, can allosterically affect function. Here we show a mechanism by which an IDP can allosterically control function by simultaneously tuning transcriptional activation and repression, using a novel strategy that relies on the principle of 'energetic frustration'...
October 12, 2017: ELife
https://www.readbyqxmd.com/read/29018974/catalytic-diversity-and-homotropic-allostery-of-two-cytochrome-p450-monooxygenase-like-proteins-from-trichoderma-brevicompactum
#17
Razak Hussain, Indu Kumari, Shikha Sharma, Mushtaq Ahmed, Tabreiz Ahmad Khan, Yusuf Akhter
Trichothecenes are the secondary metabolites produced by Trichoderma spp. Some of these molecules have been reported for their ability to stimulate plant growth by suppressing plant diseases and hence enabling Trichoderma spp. to be efficiently used as biocontrol agents in modern agriculture. Many of the proteins involved in the trichothecenes biosynthetic pathway in Trichoderma spp. are encoded by the genes present in the tri cluster. Tri4 protein catalyzes three consecutive oxygenation reaction steps during biosynthesis of isotrichodiol in the trichothecenes biosynthetic pathway, while tri11 protein catalyzes the C4 hydroxylation of 12, 13-epoxytrichothec-9-ene to produce trichodermol...
December 2017: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/28993252/h-d-exchange-mass-spectrometry-and-statistical-coupling-analysis-reveal-a-role-for-allostery-in-a-ferredoxin-dependent-bifurcating-transhydrogenase-catalytic-cycle
#18
Luke Berry, Saroj Poudel, Monika Tokmina-Lukaszewska, Daniel R Colman, Diep M N Nguyen, Gerrit J Schut, Michael W W Adams, John W Peters, Eric S Boyd, Brian Bothner
Recent investigations into ferredoxin-dependent transhydrogenases, a class of enzymes responsible for electron transport, have highlighted the biological importance of flavin-based electron bifurcation (FBEB). FBEB generates biomolecules with very low reduction potential by coupling the oxidation of an electron donor with intermediate potential to the reduction of high and low potential molecules. Bifurcating systems can generate biomolecules with very low reduction potentials, such as reduced ferredoxin (Fd), from species such as NADPH...
January 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28933661/suppressing-allostery-in-epitope-mapping-experiments-using-millisecond-hydrogen-deuterium-exchange-mass-spectrometry
#19
Bin Deng, Shaolong Zhu, Andrew M Macklin, Jianrong Xu, Cristina Lento, Adnan Sljoka, Derek J Wilson
Localization of the interface between the candidate antibody and its antigen target, commonly known as epitope mapping, is a critical component of the development of therapeutic monoclonal antibodies. With the recent availability of commercial automated systems, hydrogen / deuterium eXchange (HDX) is rapidly becoming the tool for mapping epitopes preferred by researchers in both industry and academia. However, this approach has a significant drawback in that it can be confounded by 'allosteric' structural and dynamic changes that result from the interaction, but occur far from the point(s) of contact...
November 2017: MAbs
https://www.readbyqxmd.com/read/28931607/direct-observation-of-conformational-population-shifts-in-crystalline-human-hemoglobin
#20
Naoya Shibayama, Mio Ohki, Jeremy R H Tame, Sam-Yong Park
Although X-ray crystallography is the most commonly used technique for studying the molecular structure of proteins, it is not generally able to monitor the dynamic changes or global domain motions that often underlie allostery. These motions often prevent crystal growth or reduce crystal order. We have recently discovered a crystal form of human hemoglobin that contains three protein molecules allowed to express a full range of quaternary structures, whereas maintaining strong X-ray diffraction. Here we use this crystal form to investigate the effects of two allosteric effectors, phosphate and bezafibrate, by tracking the structures and functions of the three hemoglobin molecules following the addition of each effector...
November 3, 2017: Journal of Biological Chemistry
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