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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
Aysima Hacisuleyman, Burak Erman
It has recently been proposed by Gunasakaran et al. that allostery may be an intrinsic property of all proteins. Here, we develop a computational method that can determine and quantify allosteric activity in any given protein. Based on Schreiber's transfer entropy formulation, our approach leads to an information transfer landscape for the protein that shows the presence of entropy sinks and sources and explains how pairs of residues communicate with each other using entropy transfer. The model can identify the residues that drive the fluctuations of others...
January 17, 2017: PLoS Computational Biology
Gabrielle Stetz, Gennady M Verkhivker
Allosteric interactions in the Hsp70 proteins are linked with their regulatory mechanisms and cellular functions. Despite significant progress in structural and functional characterization of the Hsp70 proteins fundamental questions concerning modularity of the allosteric interaction networks and hierarchy of signaling pathways in the Hsp70 chaperones remained largely unexplored and poorly understood. In this work, we proposed an integrated computational strategy that combined atomistic and coarse-grained simulations with coevolutionary analysis and network modeling of the residue interactions...
January 2017: PLoS Computational Biology
Anthony B Law, Paul J Sapienza, Jun Zhang, Xiaobing Zuo, Chad M Petit
Allostery enables tight regulation of protein function in the cellular environment. While existing models of allostery are firmly rooted in the current structure-function paradigm, the mechanistic basis for allostery in the absence of structural change remains unclear. In this study, we show that a typical globular protein is able to undergo significant changes in volume under native conditions while exhibiting no additional changes in protein structure. These native state volume fluctuations were found to correlate with changes in internal motions that were previously recognized as a source of allosteric entropy...
January 17, 2017: Journal of the American Chemical Society
Sharrol Bachas, Bryan Kohrs, Herschel V Wade
BmrR is a multidrug resistance regulator that responds to diverse ligands. To obtain insights into signal recognition, allosteric control and cooperativity, we employed a quantitative in vitro transcription assay to determine the ligand-dependent activation profiles for a diverse set of cations, zwitterions and uncharged ligands. Like many other biological switch systems, the data are well described by a modified Hill equation. Parameters extracted from curve fits to the data include, L50, RMAX and N. We find that L50 directly correlates to Gbind suggesting that the parameter reflects binding, whereas RMAX and N reflect allosteric control and cooperativity, respectively...
January 16, 2017: ChemMedChem
Michael Joseph Holliday, Carlo Camilloni, Geoffrey Stuart Armstrong, Michele Vendruscolo, Elan Zohar Eisenmesser
Many protein systems rely on coupled dynamic networks to allosterically regulate function. However, the broad conformational space sampled by non-coherently dynamic systems has precluded detailed analysis of their communication mechanisms. Here, we have developed a methodology that combines the high sensitivity afforded by nuclear magnetic resonance relaxation techniques and single-site multiple mutations, termed RASSMM, to identify two allosterically coupled dynamic networks within the non-coherently dynamic enzyme cyclophilin A...
December 27, 2016: Structure
Stacey-Lynn Paiva, Sara R da Silva, Elvin D de Araujo, Patrick Thomas Gunning
The labeling of proteins with ubiquitin/ubiquitin-like (Ubl) proteins is crucial for several physiological processes and in the onset of various diseases. Recently, targeting ubiquitin protein labeling has shifted towards the use of allosteric mechanisms over classical activity-based approaches. Allosteric enzyme regulation offers the potential for greater selectivity and has demonstrated less susceptibility to acquired resistance often associated with active site inhibitors. Furthermore, the isoform diversity among E1 activating, E2 conjugating, E3 ligase and deubiquitinating (DUB) enzymes offers an ideal platform for modulating activity via allostery...
January 11, 2017: Journal of Medicinal Chemistry
Agnieszka A Gil, Sergey P Laptenok, Jarrod B French, James N Iuliano, Andras Lukacs, Christopher R Hall, Igor V Sazanovich, Gregory M Greetham, Adelbert Bacher, Boris Illarionov, Markus Fischer, Peter J Tonge, Stephen R Meech
The rational engineering of photosenor proteins underpins the field of optogenetics, in which light is used for spatio-temporal control of cell signalling. Optogenetic elements function by converting electronic excitation of an embedded chromophore into structural changes on the μs-sec timescale, which then modulate the activity of output domains responsible for biological signalling. Using time resolved vibrational spectroscopy coupled with isotope labelling we have mapped the structural evolution of the LOV2 domain of the flavin binding phototropin Avena sativa (AsLOV2) over 10 decades of time, reporting structural dynamics between 100 femtoseconds and one millisecond after optical ex-citation...
January 9, 2017: Journal of Physical Chemistry. B
Felix Alexander Weyer, Andrea Gumiero, Genís Valentín Gesé, Karine Lapouge, Irmgard Sinning
Cotranslational chaperones assist de novo folding of nascent polypeptides, prevent them from aggregating and modulate translation. The ribosome-associated complex (RAC) is unique in that the Hsp40 protein Zuo1 and the atypical Hsp70 chaperone Ssz1 form a stable heterodimer, which acts as a cochaperone for the Hsp70 chaperone Ssb. Here we present the structure of the Chaetomium thermophilum RAC core comprising Ssz1 and the Zuo1 N terminus. We show how the conserved allostery of Hsp70 proteins is abolished and this Hsp70-Hsp40 pair is molded into a functional unit...
January 9, 2017: Nature Structural & Molecular Biology
Emily R Weikum, Matthew T Knuesel, Eric A Ortlund, Keith R Yamamoto
The glucocorticoid receptor (GR) is a constitutively expressed transcriptional regulatory factor (TRF) that controls many distinct gene networks, each uniquely determined by particular cellular and physiological contexts. The precision of GR-mediated responses seems to depend on combinatorial, context-specific assembly of GR-nucleated transcription regulatory complexes at genomic response elements. In turn, evidence suggests that context-driven plasticity is conferred by the integration of multiple signals, each serving as an allosteric effector of GR conformation, a key determinant of regulatory complex composition and activity...
January 5, 2017: Nature Reviews. Molecular Cell Biology
Nicholas Spellmon, Xiaonan Sun, Wen Xue, Joshua Holcomb, Srinivas Chakravarthy, Weifeng Shang, Brian Edwards, Nualpun Sirinupong, Chunying Li, Zhe Yang
SMYD3 plays a key role in cancer cell viability, adhesion, migration and invasion. SMYD3 promotes formation of inducible regulatory T cells and is involved in reducing autoimmunity. However, the nearly "closed" substrate-binding site and poor in vitro H3K4 methyltransferase activity have obscured further understanding of this oncogenically related protein. Here we reveal that SMYD3 can adopt an "open" conformation using molecular dynamics simulation and small-angle X-ray scattering. This ligand-binding-capable open state is related to the crystal structure-like closed state by a striking clamshell-like inter-lobe dynamics...
2017: AIMS Biophysics
Takato Sato, Jun Ohnuki, Mitsunori Takano
Protein uses allostery to execute biological function. The physical mechanism underlying the allostery has long been studied, with the focus on the mechanical response by ligand binding. Here, we highlight the electrostatic response, presenting an idea of "dielectric allostery". We conducted molecular dynamics simulations of myosin, a motor protein with allostery, and analyzed the response to ATP binding which is a crucial step in force-generating function, forcing myosin to unbind from the actin filament. We found that the net negative charge of ATP causes a large-scale, anisotropic dielectric response in myosin, altering the electrostatic potential in the distant actin-binding region and accordingly retracting a positively charged actin-binding loop...
December 29, 2016: Journal of Physical Chemistry. B
Padmaja Mehta-D'souza, Arkadiusz G Klopocki, Vaheh Oganesyan, Simon Terzyan, Timothy Mather, Zhenhai Li, Sumith R Panicker, Cheng Zhu, Rodger P McEver
Selectin interactions with fucosylated glycan ligands mediate leukocyte rolling in the vasculature under shear forces. Crystal structures of P- and E-selectin suggest a two-state model in which ligand binding to the lectin domain closes loop 83-89 around the Ca(2+)-coordination site, enabling Glu88 to engage Ca(2+) and fucose. This triggers further allostery that opens the lectin/EGF-domain hinge. The model posits that force accelerates transition from the bent (low-affinity) to the extended (high-affinity) state...
December 23, 2016: Journal of Biological Chemistry
Robert C Harris, Nanjie Deng, Ronald M Levy, Ryosuke Ishizuka, Nobuyuki Matubayasi
Many biomolecules undergo conformational changes associated with allostery or ligand binding. Observing these changes in computer simulations is difficult if their timescales are long. These calculations can be accelerated by observing the transition on an auxiliary free energy surface with a simpler Hamiltonian and connecting this free energy surface to the target free energy surface with free energy calculations. Here, we show that the free energy legs of the cycle can be replaced with energy representation (ER) density functional approximations...
December 23, 2016: Journal of Computational Chemistry
Wolfgang W A Schamel, Balbino Alarcon, Thomas Höfer, Susana Minguet
The activity of the αβ TCR is controlled by conformational switches. In the resting conformation, the TCR is not phosphorylated and is inactive. Binding of multivalent peptide-MHC to the TCR stabilizes the active conformation, leading to TCR signaling. These two conformations allow the TCRs to be allosterically regulated. We review recent data on heterotropic allostery where peptide-MHC and membrane cholesterol serve opposing functions as positive and negative allosteric regulators, respectively. In resting T cells cholesterol keeps TCRs in the resting conformation that otherwise would become spontaneously active...
January 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Nathaniel R Beattie, Nicholas D Keul, Andrew M Sidlo, Zachary A Wood
Human UDP-glucose dehydrogenase (hUGDH) is regulated by an atypical allosteric mechanism in which the feedback inhibitor UDP-xylose (UDP-Xyl) competes with the substrate for the active site. Binding of UDP-Xyl triggers the T131-loop/α6 allosteric switch, which converts the hexameric structure of hUGDH into an inactive, horseshoe-shaped complex (E(Ω)). This allosteric transition buries residue A136 in the protein core to produce a subunit interface that favors the E(Ω) structure. Here we use a methionine substitution to prevent the burial of A136 and trap the T131-loop/α6 switch in the active conformation...
January 10, 2017: Biochemistry
Joshua T Atkinson, Ian Campbell, George N Bennett, Jonathan J Silberg
The ferredoxin (Fd) protein family is a structurally diverse group of iron-sulfur proteins that function as electron carriers, linking biochemical pathways important for energy transduction, nutrient assimilation, and primary metabolism. While considerable biochemical information about individual Fd protein electron carriers and their reactions has been acquired, we cannot yet anticipate the proportion of electrons shuttled between different Fd-partner proteins within cells using biochemical parameters that govern electron flow, such as holo-Fd concentration, midpoint potential (driving force), molecular interactions (affinity and kinetics), conformational changes (allostery), and off-pathway electron leakage (chemical oxidation)...
December 27, 2016: Biochemistry
Maria M Villarreal, Sun Kyung Kim, Lindsey Barron, Ravi Kodali, Jason Baardsnes, Cynthia S Hinck, Troy C Krzysiak, Morkos A Henen, Olga Pakhomova, Valentín Mendoza, Maureen D O'Connor-McCourt, Eileen M Lafer, Fernando López-Casillas, Andrew P Hinck
Transforming growth factor (TGF) β1, β2, and β3 (TGF-β1-TGF-β3, respectively) are small secreted signaling proteins that each signal through the TGF-β type I and type II receptors (TβRI and TβRII, respectively). However, TGF-β2, which is well-known to bind TβRII several hundred-fold more weakly than TGF-β1 and TGF-β3, has an additional requirement for betaglycan, a membrane-anchored nonsignaling receptor. Betaglycan has two domains that bind TGF-β2 at independent sites, but how it binds TGF-β2 to potentiate TβRII binding and how the complex with TGF-β, TβRII, and betaglycan undergoes the transition to the signaling complex with TGF-β, TβRII, and TβRI are not understood...
December 13, 2016: Biochemistry
Junko Taguchi, Akio Kitao
We examine the dynamic features of non-trivial allosteric binding sites to elucidate potential drug binding sites. These allosteric sites were previously found to be allosteric after determination of the protein-drug co-crystal structure. After comprehensive search in the Protein Data Bank, we identify 10 complex structures with allosteric ligands whose structures are very similar to their functional forms. Then, possible pockets on the protein surface are searched as potential ligand binding sites. To mimic ligand binding to the pocket, complex models are generated to fill out each pocket with pseudo ligand blocks consisting of spheres...
2016: Biophysics and Physicobiology
Peter Hlavica
Cytochrome P450s (CYP) represent a superfamily of b-type hemoproteins catalyzing NAD(P)H-dependent oxidative biotransformation of a vast array of natural and xenobiotic compounds. Many eu- and prokaryotic members of this class of monooxygenases display complex non-Michaelis-Menten saturation kinetics, suggestive of homo-/heterotropic cooperativity arising from substrate-/effector-induced allosteric interactions. Here, the paradigm of multiple-ligand occupancy of the catalytic pocket in combination with enzyme oligomerization provides the most favored explanations for the atypical kinetic patterns...
February 2017: Journal of Inorganic Biochemistry
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