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https://www.readbyqxmd.com/read/27849063/vibrational-resonance-allostery-and-activation-in-rhodopsin-like-g-protein-coupled-receptors
#1
Kristina N Woods, Jürgen Pfeffer, Arpana Dutta, Judith Klein-Seetharaman
G protein-coupled receptors are a large family of membrane proteins activated by a variety of structurally diverse ligands making them highly adaptable signaling molecules. Despite recent advances in the structural biology of this protein family, the mechanism by which ligands induce allosteric changes in protein structure and dynamics for its signaling function remains a mystery. Here, we propose the use of terahertz spectroscopy combined with molecular dynamics simulation and protein evolutionary network modeling to address the mechanism of activation by directly probing the concerted fluctuations of retinal ligand and transmembrane helices in rhodopsin...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27848106/allosteric-effect-of-adenosine-triphosphate-on-peptide-recognition-by-3-5-cyclic-adenosine-monophosphate-dependent-protein-kinase-catalytic-subunits
#2
Rait Kivi, Karina Solovjova, Tõiv Haljasorg, Piret Arukuusk, Jaak Järv
The allosteric influence of adenosine triphosphate (ATP) on the binding effectiveness of a series of peptide inhibitors with the catalytic subunit of 3'5'-cyclic adenosine monophosphate dependent protein kinase was investigated, and the dependence of this effect on peptide structure was analyzed. The allosteric effect was calculated as ratio of peptide binding effectiveness with the enzyme-ATP complex and with the free enzyme, quantified by the competitive inhibition of the enzyme in the presence of ATP excess, and by the enzyme-peptide complex denaturation assay, respectively It was found that the principle "better binding-stronger allostery" holds for interactions of the studied peptides with the enzyme, indicating that allostery and peptide binding with the free enzyme are governed by the same specificity pattern...
November 15, 2016: Protein Journal
https://www.readbyqxmd.com/read/27845431/ligand-mediated-changes-in-conformational-dynamics-of-npma-implications-for-ribosomal-interactions
#3
Nilofer Husain, Nikhil Kumar Tulsian, Wang Loo Chien, Sushant Suresh, Ganesh Srinivasan Anand, J Sivaraman
Aminoglycosides are broad-spectrum antibiotics that bind to the 30S ribosomal subunit (30S) of bacteria and disrupt protein translation. NpmA, a structurally well-characterized methyltransferase identified in an E. coli clinical isolate, catalyzes methylation of 30S at A1408 of the 16S rRNA and confers aminoglycoside resistance. Using sucrose cushion centrifugation and isothermal titration calorimetry, we first confirmed the binding between NpmA and 30S. Next, we performed amide Hydrogen/Deuterium Exchange Mass Spectrometry (HDXMS) of apo NpmA and in the presence and absence of SAM/SAH...
November 15, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27818108/gating-role-of-his-72-in-tmpurl-enzyme-uncovered-by-structural-analyses-and-molecular-dynamics-simulations
#4
Biplab Ghosh, Venuka Durani Goyal
Histidine is ubiquitous in enzyme active sites but its role is often difficult to ascribe due to ambiguity of protonation state and complex electrostatic and dynamic effects involved. In this study the role of His 72 in TmPurL, a glutamine amidotransferase (GAT) enzyme, is investigated. TmPurL is a large 66kDa enzyme that works as part of an even larger (>100kDa) multi-protein complex. This enzyme complex performs an essential step in the purine biosynthesis pathway by abstracting ammonia from a glutamine molecule and channeling it 30Å away into the active site of TmPurL, incorporating it into a purine biosynthesis intermediate...
October 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27818101/defining-nadh-driven-allostery-regulating-apoptosis-inducing-factor
#5
Chris A Brosey, Chris Ho, Winnie Z Long, Sukrit Singh, Kathryn Burnett, Greg L Hura, Jay C Nix, Gregory R Bowman, Tom Ellenberger, John A Tainer
Apoptosis-inducing factor (AIF) is critical for mitochondrial respiratory complex biogenesis and for mediating necroptotic parthanatos; these functions are seemingly regulated by enigmatic allosteric switching driven by NADH charge-transfer complex (CTC) formation. Here, we define molecular pathways linking AIF's active site to allosteric switching regions by characterizing dimer-permissive mutants using small-angle X-ray scattering (SAXS) and crystallography and by probing AIF-CTC communication networks using molecular dynamics simulations...
November 2, 2016: Structure
https://www.readbyqxmd.com/read/27797506/allosteric-communication-disrupted-by-small-molecule-binding-to-the-imidazole-glycerol-phosphate-synthase-protein-protein-interface
#6
Ivan Rivalta, George P Lisi, Ning-Shiuan Snoeberger, Gregory A Manley, J Patrick Loria, Victor S Batista
Allosteric enzymes regulate a wide range of catalytic transformations, including biosynthetic mechanisms of important human pathogens, upon binding of substrate molecules to an orthosteric (or active) site and effector ligands at distant (allosteric) sites. We find that enzymatic activity can be impaired by small molecules that bind along the allosteric pathway connecting the orthosteric and allosteric sites, without competing with endogenous ligands. Non-competitive allosteric inhibitors disrupted allostery in the imidazole glycerol phosphate synthase (IGPS) enzyme from Thermotoga maritima as evidenced by nuclear magnetic resonance, microsecond time-scale molecular dynamics simulations, isothermal titration calorimetry and kinetic assays...
October 31, 2016: Biochemistry
https://www.readbyqxmd.com/read/27794633/molecular-dynamics-simulations-of-aptamer-binding-reveal-generalized-allostery-in-thrombin
#7
Jiajie Xiao, Freddie R Salsbury
Thrombin is an attractive target for antithrombotic therapy due to its central role in thrombosis and hemostasis as well as its role in inducing tumor growth, metastasis and tumor invasion. The thrombin-binding DNA aptamer (TBA), is under investigation for anticoagulant drugs. Although aptamer binding experiments have been revealed various effects on thrombin's enzymatic activities, the detailed picture of the thrombin's allostery from TBA binding is still unclear. To investigate thrombin's response to the aptamer-binding at the molecular level, we compare the mechanical properties and free energy landscapes of the free and aptamer-bound thrombin using microsecond-scale all-atom GPU-based molecular dynamics simulations...
October 31, 2016: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/27791125/unidirectional-allostery-in-the-regulatory-subunit-ri%C3%AE-facilitates-efficient-deactivation-of-protein-kinase-a
#8
Cong Guo, Huan-Xiang Zhou
The holoenzyme complex of protein kinase A is in an inactive state; activation involves ordered cAMP binding to two tandem domains of the regulatory subunit and release of the catalytic subunit. Deactivation has been less studied, during which the two cAMPs unbind from the regulatory subunit to allow association of the catalytic subunit to reform the holoenzyme complex. Unbinding of the cAMPs appears ordered as indicated by a large difference in unbinding rates from the two sites, but the cause has remained elusive given the structural similarity of the two tandem domains...
October 17, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27783504/the-remarkable-character-of-porphobilinogen-synthase
#9
Eileen K Jaffe
Porphobilinogen synthase (PBGS), also known as 5-aminolevulinate dehydratase, is an essential enzyme in the biosynthesis of all tetrapyrroles, which function in respiration, photosynthesis, and methanogenesis. Throughout evolution, PBGS adapted to a diversity of cellular niches and evolved to use an unusual variety of metal ions both for catalytic function and to control protein multimerization. With regard to the active site, some PBGSs require Zn(2+); a subset of those, including human PBGS, contain a constellation of cysteine residues that acts as a sink for the environmental toxin Pb(2+)...
October 26, 2016: Accounts of Chemical Research
https://www.readbyqxmd.com/read/27768684/long-range-signaling-in-muts-and-msh-homologs-via-switching-of-dynamic-communication-pathways
#10
Beibei Wang, Joshua Francis, Monika Sharma, Sean M Law, Alexander V Predeus, Michael Feig
Allostery is conformation regulation by propagating a signal from one site to another distal site. This study focuses on the long-range communication in DNA mismatch repair proteins MutS and its homologs where intramolecular signaling has to travel over 70 Å to couple lesion detection to ATPase activity and eventual downstream repair. Using dynamic network analysis based on extensive molecular dynamics simulations, multiple preserved communication pathways were identified that would allow such long-range signaling...
October 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/27766843/the-allostery-landscape-quantifying-thermodynamic-couplings-in-biomolecular-systems
#11
Michel Alain Cuendet, Harel Weinstein, Michael V LeVine
Allostery plays a fundamental role in most biological processes. However, little theory is available to describe it outside of two-state models. Here we use a statistical mechanical approach to show that the allosteric coupling between two collective variables is not a single number, but instead a two-dimensional thermodynamic coupling function that is directly related to the mutual information from information theory and the copula density function from probability theory. On this basis, we demonstrate how to quantify the contribution of specific energy terms to this thermodynamic coupling function, enabling an approximate decomposition that reveals the mechanism of allostery...
October 21, 2016: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/27739675/new-modalities-in-drug-therapy-modifying-ongoing-chemical-conversations-in-the-brain
#12
Terry Kenakin
The modification of ongoing chemical signaling in the brain through allosteric modification of seven transmembrane receptors offers a wealth of diverse beneficial outcomes in drug therapy. Specifically, biased agonism can emphasize beneficial signals and de-emphasize harmful signals thus increasing the effectiveness of agonists and opening up new vistas for previously precluded drug targets. In addition, the modification of natural agonism through positive and negative allostery can provide useful rejuvenation of failing systems...
October 14, 2016: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27713495/allosteric-regulation-in-nmda-receptors-revealed-by-the-genetically-encoded-photo-cross-linkers
#13
Meilin Tian, Shixin Ye
Allostery is essential to neuronal receptor function, but its transient nature poses a challenge for characterization. The N-terminal domains (NTDs) distinct from ligand binding domains are a major locus for allosteric regulation of NMDA receptors (NMDARs), where different modulatory binding sites have been observed. The inhibitor ifenprodil, and related phenylethanoamine compounds specifically targeting GluN1/GluN2B NMDARs have neuroprotective activity. However, whether they use differential structural pathways than the endogenous inhibitor Zn(2+) for regulation is unknown...
October 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27712124/leveraging-allostery-to-improve-g-protein-coupled-receptor-gpcr-directed-therapeutics-cannabinoid-receptor-1-as-a-discovery-target
#14
David R Janero, Ganesh A Thakur
Allosteric modulators of G-protein coupled receptors (GPCRs) hold the promise of improved pharmacology and safety over typical orthosteric GPCR ligands. These features are particularly relevant to the cannabinoid receptor 1 (CB1R) GPCR, since typical orthosteric CB1R ligands are associated with adverse events that limit their translational potential. Areas covered: The contextual basis for applying allostery to CB1R is considered from pharmacological, drug-discovery, and medicinal standpoints. Rational design of small-molecule CB1R allosteric modulators as potential pharmacotherapeutics would be greatly facilitated by direct experimental characterization of structure-function correlates underlying the biological activity of chemically-diverse CB1R allosteric modulators, CB1R allosteric ligand-binding binding pockets, and amino acid contact residues critical to allosteric ligand engagement and activity...
October 7, 2016: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/27708342/nonlinear-backbone-torsional-pair-correlations-in-proteins
#15
Shiyang Long, Pu Tian
Protein allostery requires dynamical structural correlations. Physical origin of which, however, remain elusive despite intensive studies during last two and half decades. Based on analysis of molecular dynamics (MD) simulation trajectories for ten proteins with different sizes and folds, we found that nonlinear backbone torsional pair (BTP) correlations, which are mainly spatially long-ranged and are dominantly executed by loop residues, exist extensively in most analyzed proteins. Examination of torsional motion for correlated BTPs suggested that such nonlinear correlations are mainly associated aharmonic torsional state transitions and in some cases strongly anisotropic local torsional motion of participating torsions, and occur on widely different and relatively longer time scales...
October 6, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27699616/backbone-and-methyl-resonance-assignments-of-the-42%C3%A2-kda-human-hsc70-nucleotide-binding-domain-in-the-adp-state
#16
Erik R P Zuiderweg, Jason E Gestwicki
Hsc70 is the constitutively expressed mammalian heat shock 70 kDa (Hsp70) cytosolic chaperone. It plays a central role in cellular proteostasis and protein trafficking. Here, we present the backbone and methyl group assignments for the 386-residue nucleotide binding domain of the human protein. This domain controls the chaperone's allostery, binds multiple co-chaperones and is the target of several classes of known chemical Hsp70 inhibitors. The NMR assignments are based on common triple resonance experiments with triple labeled protein, and on several (15)N and (13)C-resolved 3D NOE experiments with methyl-reprotonated samples...
October 3, 2016: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/27698144/disorder-drives-cooperative-folding-in-a-multidomain-protein
#17
Dominika T Gruszka, Carolina A T F Mendonça, Emanuele Paci, Fiona Whelan, Judith Hawkhead, Jennifer R Potts, Jane Clarke
Many human proteins contain intrinsically disordered regions, and disorder in these proteins can be fundamental to their function-for example, facilitating transient but specific binding, promoting allostery, or allowing efficient posttranslational modification. SasG, a multidomain protein implicated in host colonization and biofilm formation in Staphylococcus aureus, provides another example of how disorder can play an important role. Approximately one-half of the domains in the extracellular repetitive region of SasG are intrinsically unfolded in isolation, but these E domains fold in the context of their neighboring folded G5 domains...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27693059/bidirectional-allosteric-communication-between-the-atp-binding-site-and-the-regulatory-pif-pocket-in-pdk1-protein-kinase
#18
Jörg O Schulze, Giorgio Saladino, Katrien Busschots, Sonja Neimanis, Evelyn Süß, Dalibor Odadzic, Stefan Zeuzem, Valerie Hindie, Amanda K Herbrand, María-Natalia Lisa, Pedro M Alzari, Francesco L Gervasio, Ricardo M Biondi
Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates...
October 20, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27618662/activation-by-allostery-in-cell-wall-remodeling-by-a-modular-membrane-bound-lytic-transglycosylase-from-pseudomonas-aeruginosa
#19
Teresa Domínguez-Gil, Mijoon Lee, Iván Acebrón-Avalos, Kiran V Mahasenan, Dusan Hesek, David A Dik, Byungjin Byun, Elena Lastochkin, Jed F Fisher, Shahriar Mobashery, Juan A Hermoso
Bacteria grow and divide without loss of cellular integrity. This accomplishment is notable, as a key component of their cell envelope is a surrounding glycopeptide polymer. In Gram-negative bacteria this polymer-the peptidoglycan-grows by the difference between concurrent synthesis and degradation. The regulation of the enzymatic ensemble for these activities is poorly understood. We report herein the structural basis for the control of one such enzyme, the lytic transglycosylase MltF of Pseudomonas aeruginosa...
October 4, 2016: Structure
https://www.readbyqxmd.com/read/27607077/computational-approaches-to-investigating-allostery
#20
Ora Schueler-Furman, Shoshana J Wodak
Allosteric regulation plays a key role in many biological processes, such as signal transduction, transcriptional regulation, and many more. It is rooted in fundamental thermodynamic and dynamic properties of macromolecular systems that are still poorly understood and are moreover modulated by the cellular context. Here we review the computational approaches used in the investigation of allosteric processes in protein systems. We outline how the models of allostery have evolved from their initial formulation in the sixties to the current views, which more fully account for the roles of the thermodynamic and dynamic properties of the system...
September 5, 2016: Current Opinion in Structural Biology
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