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https://www.readbyqxmd.com/read/28537745/deciphering-cryptic-binding-sites-on-proteins-by-mixed-solvent-molecular-dynamics
#1
S Roy Kimura, Haipeng Hu, Anatoly M Ruvinsky, Woody B Sherman, Angelo D Favia
In recent years, molecular dynamics simulations of proteins in explicit mixed-solvents have been applied to various problems in protein biophysics and drug discovery, including protein folding, protein surface characterization, fragment screening, allostery, and druggability assessment. In this study, we perform a systematic study on how mixtures of organic solvent probes in water can reveal cryptic ligand binding pockets that are not evident in crystal structures of apo proteins. We examine a diverse set of eight PDB proteins that show pocket opening induced by ligand binding and investigate whether solvent MD simulations on the apo structures can induce the binding site observed in the holo structures...
May 24, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28532213/what-do-structures-tell-us-about-chemokine-receptor-function-and-antagonism
#2
Irina Kufareva, Martin Gustavsson, Yi Zheng, Bryan S Stephens, Tracy M Handel
Chemokines and their cell surface G protein-coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs...
May 22, 2017: Annual Review of Biophysics
https://www.readbyqxmd.com/read/28522638/a-self-consistent-structural-perturbation-approach-for-determining-the-magnitude-and-extent-of-allosteric-coupling-in-proteins
#3
Nandakumar Rajasekaran, Athi N Naganathan
Elucidating the extent of energetic coupling between residues in single-domain proteins, a fundamental determinant of allostery, information transfer and folding cooperativity, has remained a grand challenge. While several sequence- and structure-based approaches have been proposed, a self-consistent description that is simultaneously compatible with unfolding thermodynamics is lacking. We had recently developed a simple structural perturbation protocol that captures the changes in thermodynamic stabilities induced by point mutations within the protein interior...
May 18, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28507717/dynamic-structural-and-thermodynamic-basis-of-insulin-like-growth-factor-1-kinase-allostery-mediated-by-activation-loop-phosphorylation
#4
Yaozong Li, Kwangho Nam
Despite the importance of kinases' catalytic activity regulation in cell signaling, detailed mechanisms underlying their activity regulation are poorly understood. Herein, using insulin-like growth factor 1 receptor kinase (IGF-1RK) as a model, the mechanisms of kinase regulation by its activation loop (A-loop) phosphorylation were investigated through molecular dynamics (MD) and alchemical free energy simulations. Analyses of the simulation results and free energy landscapes determined for the entire catalytic cycle of the kinase revealed that A-loop phosphorylation affects each step in the IGF-1RK catalytic cycle, including conformational change, substrate binding/product release and catalytic phosphoryl transfer...
May 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28507681/complementary-oligonucleotides-regulate-induced-fit-ligand-binding-in-duplexed-aptamers
#5
Jeffrey D Munzar, Andy Ng, Mario Corrado, David Juncker
Duplexed aptamers (DAs) are engineered by hybridizing an aptamer-complementary element (ACE, e.g. a DNA oligonucleotide) to an aptamer; to date, ACEs have been presumed to sequester the aptamer into a non-binding duplex state, in line with a conformational selection-based model of ligand binding. Here, we uncover that DAs can actively bind a ligand from the duplex state through an ACE-regulated induced fit mechanism. Using a widely-studied ATP DNA aptamer and a solution-based equilibrium assay, DAs were found to exhibit affinities up to 1 000 000-fold higher than predicted by conformational selection alone, with different ACEs regulating the level of induced fit binding, as well as the cooperative allostery of the DA (Hill slope of 1...
March 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28505454/perturbation-response-scanning-reveals-key-residues-for-allosteric-control-in-hsp70
#6
David Penkler, Ozge Sensoy, Canan Atilgan, Ozlem Tastan Bishop
Hsp70 molecular chaperones play an important role in maintaining cellular homeostasis, and are implicated in a wide array of cellular processes including protein recovery from aggregates, cross membrane protein translocation, and protein biogenesis. Hsp70 consists of two domains, a nucleotide binding domain (NBD) and a substrate binding domain (SBD), each of which communicates via an allosteric mechanism such that the protein interconverts between two functional states, an ATP bound open conformation and an ADP bound closed conformation...
May 15, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28489401/a-molecular-dynamics-markov-state-model-of-protein-ligand-binding-and-allostery-in-crib-pdz-conformational-selection-and-induced-fit
#7
Kelly Marie Thayer, Bharat Lakhani, David L Beveridge
Conformational selection and induced fit are well-known contributors to ligand binding and allosteric effects in proteins. Molecular dynamics (MD) simulations now enable the theoretical study of protein-ligand binding in terms of ensembles of interconverting microstates and the population shifts characteristic of "dynamical allostery." Here we investigate protein-ligand binding and allostery based on a Markov State Model (MSM) with states and rates obtained from all-atom MD simulations. As an exemplary case, we consider the single domain protein par-6 PDZ with and without ligand and allosteric effector...
May 10, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28483383/applications-of-nmr-and-computational-methodologies-to-study-protein-dynamics
#8
REVIEW
Chitra Narayanan, Khushboo Bafna, Louise D Roux, Pratul K Agarwal, Nicolas Doucet
Overwhelming evidence now illustrates the defining role of atomic-scale protein flexibility in biological events such as allostery, cell signaling, and enzyme catalysis. Over the years, spin relaxation nuclear magnetic resonance (NMR) has provided significant insights on the structural motions occurring on multiple time frames over the course of a protein life span. The present review article aims to illustrate to the broader community how this technique continues to shape many areas of protein science and engineering, in addition to being an indispensable tool for studying atomic-scale motions and functional characterization...
May 5, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28459139/exploring-the-limits-of-the-usefulness-of-mutagenesis-in-studies-of-allosteric-mechanisms
#9
Qingling Tang, Aileen Y Alontaga, Todd Holyoak, Aron W Fenton
The outcome of structure-guided mutational analyses are often used in support of postulated mechanisms of protein allostery. However, the limits of how informative mutations can be in understanding allosteric mechanisms are not completely clear. Here, we report an exercise to evaluate if mutational data can support a simplistic mechanistic model, developed with minimal data inputs. Due to the lack of a mechanism to explain how alanine allosterically modifies the affinity of human liver pyruvate kinase (hL-PYK; approved symbol PKLR) for its substrate, phosphoenolpyruvate (PEP), we proposed a speculative allosteric mechanism for this system...
April 29, 2017: Human Mutation
https://www.readbyqxmd.com/read/28435869/a-dynamic-hydrophobic-core-orchestrates-allostery-in-protein-kinases
#10
Jonggul Kim, Lalima G Ahuja, Fa-An Chao, Youlin Xia, Christopher L McClendon, Alexandr P Kornev, Susan S Taylor, Gianluigi Veglia
Eukaryotic protein kinases (EPKs) constitute a class of allosteric switches that mediate a myriad of signaling events. It has been postulated that EPKs' active and inactive states depend on the structural architecture of their hydrophobic cores, organized around two highly conserved spines: C-spine and R-spine. How the spines orchestrate the transition of the enzyme between catalytically uncommitted and committed states remains elusive. Using relaxation dispersion nuclear magnetic resonance spectroscopy, we found that the hydrophobic core of the catalytic subunit of protein kinase A, a prototypical and ubiquitous EPK, moves synchronously to poise the C subunit for catalysis in response to binding adenosine 5'-triphosphate...
April 2017: Science Advances
https://www.readbyqxmd.com/read/28434917/conformational-dynamics-and-allostery-in-e2-e3-interactions-drive-ubiquitination-gp78-and-ube2g2
#11
Kalyan S Chakrabarti, Jess Li, Ranabir Das, R Andrew Byrd
Conformational dynamics plays a fundamental role in molecular recognition and activity in enzymes. The ubiquitin-conjugating enzyme (E2) Ube2g2 functions with the ubiquitin ligase (E3) gp78 to assemble poly-ubiquitin chains on target substrates. Two domains in gp78, RING and G2BR, bind to two distant regions of Ube2g2, and activate it for ubiquitin (Ub) transfer. G2BR increases the affinity between the RING and Ube2g2 by 50-fold, while the RING catalyzes the transfer of Ub from the Ube2g2∼Ub conjugate. How G2BR and RING activate Ube2g2 is unclear...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28431259/allosteric-regulation-of-metabolism-in-cancer-endogenous-mechanisms-and-considerations-for-drug-design
#12
REVIEW
Jamie A Macpherson, Dimitrios Anastasiou
Alterations in metabolic processes have been linked to various diseases, including cancer. Although gene expression can dictate long-term metabolic adaptation, many metabolic changes found in cancer are associated with altered allosteric properties of the underlying enzymes. Small molecule-protein interactions and intracellular signalling converge to orchestrate these allosteric mechanisms, which, emerging evidence suggests, constitute a promising therapeutic avenue. In this review we focus on glucose and energy metabolism to illustrate the role of allostery in cancer physiology and we discuss approaches to streamline the process of targeting aberrant allosteric pathways with small molecules...
April 18, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28430446/piecing-together-the-allosteric-patterns-of-chaperonin-groel
#13
Jin Chen, Qian Zhang, Weitong Ren, Wenfei Li
Despite considerable efforts, elucidating the allostery of large macromolecular assemblies at a molecular level in solution remains technically challenging due to its structural complexity. Here we have employed an approach combining amide backbone hydrogen/deuterium exchange coupled with mass spectrometry, fluorescence spectroscopy, and molecular simulations to characterize allosteric patterns of chaperonin GroEL, an ∼800 kDa tetradecamer from E. coli. Using available crystal structures of GroEL, we quantitatively map out GroEL allosteric changes in solution by resolving exchange behaviors of 133 overlapping proteolytic peptides with more than 95% sequence coverage...
May 4, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28428246/key-features-of-an-hsp70-chaperone-allosteric-landscape-revealed-by-ion-mobility-native-mass-spectrometry-and-double-electron-electron-resonance
#14
Alex L Lai, Eugenia M Clerico, Mandy E Blackburn, Nisha A Patel, Carol V Robinson, Peter P Borbat, Jack H Freed, Lila M Gierasch
Proteins are dynamic entities that populate conformational ensembles, and most functions of proteins depend on their dynamic character. Allostery, in particular, relies on ligand-modulated shifts in these conformational ensembles. Hsp70s are allosteric molecular chaperones with conformational landscapes that involve large rearrangements of their two domains (viz, the nucleotide-binding domain and substrate-binding domain) in response to adenine nucleotides and substrates. However, it remains unclear how the Hsp70 conformational ensemble is populated at each point of the allosteric cycle and how ligands control these populations...
April 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28425706/allosteric-autoinhibition-pathway-in-transcription-factor-erg-dynamics-network-and-mutant-experimental-evaluations
#15
Wei Ye, Tianle Qian, Hao Liu, Ray Luo, Hai-Feng Chen
Allosteric autoinhibition exists in many transcription factors. The ERG proteins exhibit autoinhibition on DNA binding by the C-terminal and N-terminal inhibitory domains (CID and NID). However, the autoinhibition mechanism and allosteric pathway of ERG are unknown. In this study we intend to elucidate the residue-level allosteric mechanism and pathway via a combined approach of computational and experimental analyses. Specifically computational residue-level fluctuation correlation data was analyzed to reveal detailed dynamics signatures in the allosteric autoinhibition process...
April 25, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28420785/bringing-disorder-and-dynamics-in-protein-allostery-into-focus
#16
A Joshua Wand
No abstract text is available yet for this article.
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28419415/allostery-at-opioid-receptors-modulation-with-small-molecule-ligands
#17
REVIEW
Kathryn E Livingston, John R Traynor
Opioid receptors are 7-transmembrane domain receptors that couple to heterotrimeric G proteins. The endogenous ligands for opioid receptors are peptides which bind to the orthosteric site on the receptors. The μ-opioid receptor is the target for opioid analgesics while the δ-opioid receptor has been suggested as a target for pain management, migraine, and depression. Similarly, κ-opioid receptors are involved in pain and depression and nociceptin receptors in pain and mood behaviors. However, exogenous orthosteric ligands for the opioid receptors cause a myriad of on-target side effects...
April 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28416647/identifiability-reducibility-and-adaptability-in-allosteric-macromolecules
#18
Gergő Bohner, Gaurav Venkataraman
The ability of macromolecules to transduce stimulus information at one site into conformational changes at a distant site, termed "allostery," is vital for cellular signaling. Here, we propose a link between the sensitivity of allosteric macromolecules to their underlying biophysical parameters, the interrelationships between these parameters, and macromolecular adaptability. We demonstrate that the parameters of a canonical model of the mSlo large-conductance Ca(2+)-activated K(+) (BK) ion channel are non-identifiable with respect to the equilibrium open probability-voltage relationship, a common functional assay...
May 1, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28412959/opportunities-for-developing-therapies-for-rare-genetic-diseases-focus-on-gain-of-function-and-allostery
#19
Binbin Chen, Russ B Altman
BACKGROUND: Advances in next generation sequencing technologies have revolutionized our ability to discover the causes of rare genetic diseases. However, developing treatments for these diseases remains challenging. In fact, when we systematically analyze the US FDA orphan drug list, we find that only 8% of rare diseases have an FDA-designated drug. Our approach leverages three primary insights: first, diseases with gain-of-function mutations and late onset are more likely to have drug options; second, drugs are more often inhibitors than activators; and third, some disease-causing proteins can be rescued by allosteric activators in diseases due to loss-of-function mutations...
April 17, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28411213/allostery-modulates-the-beat-rate-of-a-cardiac-pacemaker
#20
Chung-Jung Tsai, Ruth Nussinov
The S672R mutation in heart cell ion channels leads to low heart rates and arrhythmia by an unknown route. A multifaceted NMR analysis now demonstrates that this mutant impacts allosteric coupling in domains inside of the cell to change channel activation, providing a mechanistic explanation for phenotypic outcomes.
April 14, 2017: Journal of Biological Chemistry
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