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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
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
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
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
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
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
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
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
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
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
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
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
Modupeola A Sowole, Sarah Simpson, Yulia V Skovpen, David R J Palmer, Lars Konermann
Dihydrodipicolinate synthase is a tetrameric enzyme of the diaminopimelate pathway in bacteria and plants. The protein catalyzes the condensation of pyruvate (Pyr) and aspartate semialdehyde en route to the end product lysine (Lys). Dihydrodipicolinate synthase from Campylobacter jejuni (CjDHDPS) is allosterically inhibited by Lys. CjDHDPS is a promising antibiotic target, as highlighted by the recent development of a potent bis-lysine (bisLys) inhibitor. The mechanism whereby Lys and bisLys allosterically inhibit CjDHDPS remains poorly understood...
September 27, 2016: Biochemistry
Stuart J Edelstein, Jean-Pierre Changeux
G-protein-coupled receptors (GPCRs) constitute a large group of integral membrane proteins that transduce extracellular signals from a wide range of agonists into targeted intracellular responses. Although the responses can vary depending on the category of G-proteins activated by a particular receptor, responses were also found to be triggered by interactions of the receptor with β-arrestins. It was subsequently discovered that for the same receptor molecule (e.g., the β-adrenergic receptor), some agonists have a propensity to specifically favor responses by G-proteins, others by β-arrestins, as has now been extensively studied...
September 6, 2016: Biophysical Journal
Xiaomin Ma, Hu Meng, Luhua Lai
Allostery is the phenomenon in which a ligand binding at one site affects other sites in the same macromolecule. Allostery has important roles in many biological processes. Theoretically, all nonfibrous proteins are potentially allosteric. However, few allosteric proteins have been validated, and the identification of novel allosteric sites remains a challenge. The motion of residues and subunits underlies protein function; therefore, we hypothesized that the motions of allosteric and orthosteric sites are correlated...
September 26, 2016: Journal of Chemical Information and Modeling
Jun Ohnuki, Takato Sato, Mitsunori Takano
Allostery is indispensable for a protein to work, where a locally applied stimulus is transmitted to a distant part of the molecule. While the allostery due to chemical stimuli such as ligand binding has long been studied, the growing interest in mechanobiology prompts the study of the mechanically stimulated allostery, the physical mechanism of which has not been established. By molecular dynamics simulation of a motor protein myosin, we found that a locally applied mechanical stimulus induces electrostatic potential change at distant regions, just like the piezoelectricity...
July 2016: Physical Review. E
Francesco Ricci, Alexis Vallée-Bélisle, Anna J Simon, Alessandro Porchetta, Kevin W Plaxco
The biosensor community has long focused on achieving the lowest possible detection limits, with specificity (the ability to differentiate between closely similar target molecules) and sensitivity (the ability to differentiate between closely similar target concentrations) largely being relegated to secondary considerations and solved by the inclusion of cumbersome washing and dilution steps or via careful control experimental conditions. Nature, in contrast, cannot afford the luxury of washing and dilution steps, nor can she arbitrarily change the conditions (temperature, pH, ionic strength) under which binding occurs in the homeostatically maintained environment within the cell...
September 20, 2016: Accounts of Chemical Research
B R C Amor, M T Schaub, S N Yaliraki, M Barahona
Allostery is a fundamental mechanism of biological regulation, in which binding of a molecule at a distant location affects the active site of a protein. Allosteric sites provide targets to fine-tune protein activity, yet we lack computational methodologies to predict them. Here we present an efficient graph-theoretical framework to reveal allosteric interactions (atoms and communication pathways strongly coupled to the active site) without a priori information of their location. Using an atomistic graph with energy-weighted covalent and weak bonds, we define a bond-to-bond propensity quantifying the non-local effect of instantaneous bond fluctuations propagating through the protein...
2016: Nature Communications
Cheng Lu, Gerhard Stock, Volker Knecht
A local perturbation of a protein may lead to functional changes at some distal site, a phenomenon denoted as allostery. Here we study the allosteric control of a protease using molecular dynamics simulations. The system considered is the bacterial protein DegS which includes a protease domain activated upon ligand binding to an adjacent PDZ domain. Starting from crystallographic structures of DegS homo-trimers, we perform simulations of the ligand-free and -bound state of DegS at equilibrium. Con- sidering a single protomer only, the trimeric state was mimicked by applying restraints on the residues in contact with other protomers in the DegS trimer...
August 24, 2016: Proteins
Sun-Joo Lee, Feifei Ren, Eva-Maria Zangerl-Plessl, Sarah Heyman, Anna Stary-Weinzinger, Peng Yuan, Colin G Nichols
Inward rectifier potassium (Kir) channel activity is controlled by plasma membrane lipids. Phosphatidylinositol-4,5-bisphosphate (PIP2) binding to a primary site is required for opening of classic inward rectifier Kir2.1 and Kir2.2 channels, but interaction of bulk anionic phospholipid (PL(-)) with a distinct second site is required for high PIP2 sensitivity. Here we show that introduction of a lipid-partitioning tryptophan at the second site (K62W) generates high PIP2 sensitivity, even in the absence of PL(-) Furthermore, high-resolution x-ray crystal structures of Kir2...
September 2016: Journal of General Physiology
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