keyword
MENU ▼
Read by QxMD icon Read
search

allostery

keyword
https://www.readbyqxmd.com/read/29777683/probing-the-binding-site-of-novel-selective-positive-allosteric-modulators-at-the-m-1-machr
#1
Elham Khajehali, Celine Valant, Manuela Jörg, Andrew B Tobin, P Jeffrey Conn, Craig W Lindsley, Patrick M Sexton, Peter J Scammells, Arthur Christopoulos
Subtype-selective allosteric modulation of the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) is an attractive approach for the treatment of numerous disorders, including cognitive deficits. The discovery of benzyl quinolone carboxylic acid, BQCA, a selective M1 mAChR positive allosteric modulator (PAM), spurred the subsequent development of newer generation M1 PAMs representing diverse chemical scaffolds, different pharmacodynamic properties and, in some instances, improved pharmacokinetics. Key exemplar molecules from such efforts include PF-06767832 (N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-5-methyl-4-(4-(thiazol-4-yl)benzyl)pyridine-2-carboxamide), VU6004256 (4,6-difluoro-N-(1S,2S)-2-hydroxycyclohexyl-1-((6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl)methyl)-1H-indole-3-carboxamide) and MIPS1780 (3-(2-hydroxycyclohexyl)-6-(2-((4-(1-methyl-1H-pyrazol-4-yl)-benzyl)oxy)phenyl)pyrimidin-4(3H)-one)...
May 16, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29765611/intermolecular-correlations-are-necessary-to-explain-diffuse-scattering-from-protein-crystals
#2
Ariana Peck, Frédéric Poitevin, Thomas J Lane
Conformational changes drive protein function, including catalysis, allostery and signaling. X-ray diffuse scattering from protein crystals has frequently been cited as a probe of these correlated motions, with significant potential to advance our understanding of biological dynamics. However, recent work has challenged this prevailing view, suggesting instead that diffuse scattering primarily originates from rigid-body motions and could therefore be applied to improve structure determination. To investigate the nature of the disorder giving rise to diffuse scattering, and thus the potential applications of this signal, a diverse repertoire of disorder models was assessed for its ability to reproduce the diffuse signal reconstructed from three protein crystals...
March 1, 2018: IUCrJ
https://www.readbyqxmd.com/read/29764935/the-disorderly-conduct-of-hsc70-and-its-interaction-with-the-alzheimer-s-related-tau-protein
#3
Isabelle R Taylor, Atta Ahmad, Taia Wu, Bryce A Nordhues, Anup Bhullar, Jason E Gestwicki, Erik R P Zuiderweg
Hsp70 chaperones bind to various protein substrates for folding, trafficking, and degradation. Considerable structural information is available about how prokaryotic Hsp70 (DnaK) binds substrates, but less is known about mammalian Hsp70s, of which there are 13 isoforms encoded in the human genome. Here, we report the interaction between the human Hsp70 isoform heat shock cognate 71 KDa protein (Hsc70 or HSPA8) and peptides derived from the microtubule-associated protein tau, which is linked to Alzheimer's disease...
May 15, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29757429/allofinder-a-strategy-for-allosteric-modulator-discovery-and-allosterome-analyses
#4
Min Huang, Kun Song, Xinyi Liu, Shaoyong Lu, Qiancheng Shen, Renxiao Wang, Jingze Gao, Yuanyuan Hong, Qian Li, Duan Ni, Jianrong Xu, Guoqiang Chen, Jian Zhang
Allostery tweaks innumerable biological processes and plays a fundamental role in human disease and drug discovery. Exploration of allostery has thus been regarded as a crucial requirement for research on biological mechanisms and the development of novel therapeutics. Here, based on our previously developed allosteric data and methods, we present an interactive platform called AlloFinder that identifies potential endogenous or exogenous allosteric modulators and their involvement in human allosterome. AlloFinder automatically amalgamates allosteric site identification, allosteric screening and allosteric scoring evaluation of modulator-protein complexes to identify allosteric modulators, followed by allosterome mapping analyses of predicted allosteric sites and modulators in human proteome...
May 11, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29735743/the-substrate-specificity-of-eukaryotic-cytosolic-chaperonin-cct
#5
REVIEW
Keith R Willison
The cytosolic chaperonin CCT (chaperonin containing TCP-1) is an ATP-dependent double-ring protein machine mediating the folding of members of the eukaryotic cytoskeletal protein families. The actins and tubulins are obligate substrates of CCT because they are completely dependent on CCT activity to reach their native states. Genetic and proteomic analysis of the CCT interactome in the yeast Saccharomyces cerevisiae revealed a CCT network of approximately 300 genes and proteins involved in many fundamental biological processes...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735742/interplay-of-self-association-and-conformational-flexibility-in-regulating-protein-function
#6
REVIEW
Michael Garton, Stephen S MacKinnon, Anatoly Malevanets, Shoshana J Wodak
Many functional roles have been attributed to homodimers, the most common mode of protein self-association, notably in the regulation of enzymes, ion channels, transporters and transcription factors. Here we review findings that offer new insights into the different roles conformational flexibility plays in regulating homodimer function. Intertwined homodimers of two-domain proteins and their related family members display significant conformational flexibility, which translates into concerted motion between structural domains...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735741/folding-cooperativity-and-allosteric-function-in-the-tandem-repeat-protein-class
#7
REVIEW
Albert Perez-Riba, Marie Synakewicz, Laura S Itzhaki
The term allostery was originally developed to describe structural changes in one binding site induced by the interaction of a partner molecule with a distant binding site, and it has been studied in depth in the field of enzymology. Here, we discuss the concept of action at a distance in relation to the folding and function of the solenoid class of tandem-repeat proteins such as tetratricopeptide repeats (TPRs) and ankyrin repeats. Distantly located repeats fold cooperatively, even though only nearest-neighbour interactions exist in these proteins...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735740/a-non-equilibrium-approach-to-allosteric-communication
#8
REVIEW
Gerhard Stock, Peter Hamm
While the theory of protein folding is well developed, including concepts such as rugged energy landscape, folding funnel, etc., the same degree of understanding has not been reached for the description of the dynamics of allosteric transitions in proteins. This is not only due to the small size of the structural change upon ligand binding to an allosteric site, but also due to challenges in designing experiments that directly observe such an allosteric transition. On the basis of recent pump-probe-type experiments (Buchli et al...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735739/the-allosteron-model-for-entropic-allostery-of-self-assembly
#9
Tom McLeish, C Schaefer, A C von der Heydt
Using the simple 'allosteron' model, we show that it is possible, in principle, to elicit pathways by which fluctuation allostery affects self-assembly of protein complexes. We treat the cases of (i) protein fibrils and nucleation, (ii) n -mer protein complexes, and (iii) weakly attractive allosteric interactions in protein-like soft nanoscale objects that can be tuned to define exclusive self-associating families.This article is part of a discussion meeting issue 'Allostery and molecular machines'.
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735738/ancient-thioredoxins-evolved-to-modern-day-stability-function-requirement-by-altering-native-state-ensemble
#10
Tushar Modi, Jonathan Huihui, Kingshuk Ghosh, S Banu Ozkan
Thioredoxins (THRXs)-small globular proteins that reduce other proteins-are ubiquitous in all forms of life, from Archaea to mammals. Although ancestral thioredoxins share sequential and structural similarity with the modern-day (extant) homologues, they exhibit significantly different functional activity and stability. We investigate this puzzle by comparative studies of their (ancient and modern-day THRXs') native state ensemble, as quantified by the dynamic flexibility index (DFI), a metric for the relative resilience of an amino acid to perturbations in the rest of the protein...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735737/intra-molecular-pathways-of-allosteric-control-in-hsp70s
#11
REVIEW
Matthias P Mayer
The 70 kDa heat-shock protein (Hsp70) is undoubtedly the most versatile of all molecular chaperones. Hsp70 is involved in numerous cellular protein folding processes, accompanying proteins throughout their lifespan from de novo folding at the ribosome to degradation at the proteasome, surveilling protein stability and functionality. Several properties of this ATP-dependent chaperone constitute the molecular basis for this versatility. With its substrate binding domain (SBD), Hsp70 transiently interacts with a short degenerative linear sequence motif found practically in all proteins and, in addition, with more folded protein conformers...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735736/signalling-networks-and-dynamics-of-allosteric-transitions-in-bacterial-chaperonin-groel-implications-for-iterative-annealing-of-misfolded-proteins
#12
REVIEW
D Thirumalai, Changbong Hyeon
Signal transmission at the molecular level in many biological complexes occurs through allosteric transitions. Allostery describes the responses of a complex to binding of ligands at sites that are spatially well separated from the binding region. We describe the structural perturbation method, based on phonon propagation in solids, which can be used to determine the signal-transmitting allostery wiring diagram (AWD) in large but finite-sized biological complexes. Application to the bacterial chaperonin GroEL-GroES complex shows that the AWD determined from structures also drives the allosteric transitions dynamically...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735735/molecular-switch-like-regulation-in-motor-proteins
#13
REVIEW
Sara Tafoya, Carlos Bustamante
Motor proteins are powered by nucleotide hydrolysis and exert mechanical work to carry out many fundamental biological tasks. To ensure their correct and efficient performance, the motors' activities are allosterically regulated by additional factors that enhance or suppress their NTPase activity. Here, we review two highly conserved mechanisms of ATP hydrolysis activation and repression operating in motor proteins-the glutamate switch and the arginine finger-and their associated regulatory factors. We examine the implications of these regulatory mechanisms in proteins that are formed by multiple ATPase subunits...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735734/substrate-protein-dependence-of-groel-groes-interaction-cycle-revealed-by-high-speed-atomic-force-microscopy-imaging
#14
Daisuke Noshiro, Toshio Ando
A double-ring-shaped tetradecameric GroEL complex assists proper protein folding in cooperation with the cochaperonin GroES. The dynamic GroEL-GroES interaction reflects the allosteric intra- and inter-ring communications and the chaperonin reaction. Therefore, revealing this dynamic interaction is essential to understanding the allosteric communications and the operation mechanism of GroEL. Nevertheless, how this interaction proceeds in the chaperonin cycle has long been controversial. Here, we directly image the dynamic GroEL-GroES interaction under conditions with and without foldable substrate protein using high-speed atomic force microscopy...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735733/the-groel-chaperonin-a-protein-machine-with-pistons-driven-by-atp-binding-and-hydrolysis
#15
George H Lorimer, Xue Fei, Xiang Ye
In response to the binding of ATP, the two heptameric rings of the GroEL chaperonin protein interact with one another in a negatively cooperative manner. Owing to the helix dipole, the positively charged nitrogen of glycine 88 at the N-terminus of helix D binds to oxygen atoms on the β and γ phosphorus atoms of ATP. In apo-GroEL, the nucleotide-binding sites of different rings are connected to one another by the interaction of the ɛ-amino group of lysine 105 of one helix D across the twofold axis with the negatively charged carbonyl oxygen atom of alanine 109 at the C-terminus of the other helix D...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735732/markov-models-for-the-elucidation-of-allosteric-regulation
#16
REVIEW
Ushnish Sengupta, Birgit Strodel
Allosteric regulation refers to the process where the effect of binding of a ligand at one site of a protein is transmitted to another, often distant, functional site. In recent years, it has been demonstrated that allosteric mechanisms can be understood by the conformational ensembles of a protein. Molecular dynamics (MD) simulations are often used for the study of protein allostery as they provide an atomistic view of the dynamics of a protein. However, given the wealth of detailed information hidden in MD data, one has to apply a method that allows extraction of the conformational ensembles underlying allosteric regulation from these data...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735731/shared-dynamics-of-leut-superfamily-members-and-allosteric-differentiation-by-structural-irregularities-and-multimerization
#17
Luca Ponzoni, She Zhang, Mary Hongying Cheng, Ivet Bahar
The LeuT-fold superfamily includes secondary active transporters from different functional families, which share a common tertiary structure, despite having a remarkably low sequence similarity. By identifying the common structural and dynamical features upon principal component analysis of a comprehensive ensemble of 90 experimentally resolved structures and anisotropic network model evaluation of collective motions, we provide a unified point of view for understanding the reasons why this particular fold has been selected by evolution to accomplish such a broad spectrum of functions...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735730/unpicking-allosteric-mechanisms-of-homo-oligomeric-proteins-by-determining-their-successive-ligand-binding-constants
#18
REVIEW
Ranit Gruber, Amnon Horovitz
Advances in native mass spectrometry and single-molecule techniques have made it possible in recent years to determine the values of successive ligand binding constants for large multi-subunit proteins. Given these values, it is possible to distinguish between different allosteric mechanisms and, thus, obtain insights into how various bio-molecular machines work. Here, we describe for ring-shaped homo-oligomers, in particular, how the relationship between the values of successive ligand binding constants is diagnostic for concerted, sequential and probabilistic allosteric mechanisms...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735729/ensemble-allosteric-model-energetic-frustration-within-the-intrinsically-disordered-glucocorticoid-receptor
#19
REVIEW
Jordan T White, Jing Li, Emily Grasso, James O Wrabl, Vincent J Hilser
Allostery is an important regulatory phenomenon enabling precise control of biological function. Initial understanding of allostery was gained from seminal work on conformational changes exhibited by structured proteins. Within the last decade, protein allostery has also been demonstrated to occur within intrinsically disordered proteins. This emerging concept of disorder-mediated allostery can be usefully understood in the context of a thermodynamic ensemble. The advantage of this ensemble allosteric model is that it unifies the explanations of allostery occurring within both structured and disordered proteins...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29735728/the-nicotinic-acetylcholine-receptor-a-typical-allosteric-machine
#20
REVIEW
Jean-Pierre Changeux
The concept of allosteric interaction was initially proposed to account for the inhibitory feedback mechanism mediated by bacterial regulatory enzymes. In contrast with the classical mechanism of competitive, steric, interaction between ligands for a common site, allosteric interactions take place between topographically distinct sites and are mediated by a discrete and reversible conformational change of the protein. The concept was soon extended to membrane receptors for neurotransmitters and shown to apply to the signal transduction process which, in the case of the acetylcholine nicotinic receptor (nAChR), links the ACh binding site to the ion channel...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
keyword
keyword
59611
1
2
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"