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https://www.readbyqxmd.com/read/28933661/suppressing-allostery-in-epitope-mapping-experiments-using-millisecond-hydrogen-deuterium-exchange-mass-spectrometry
#1
Bin Deng, Shaolong Zhu, Andrew M Macklin, Jianrong Xu, Cristina Lento, Adnan Sljoka, Derek J Wilson
Localization of the interface between the candidate antibody and its antigen target, commonly known as epitope mapping, is a critical component of the development of therapeutic monoclonal antibodies. With the recent availability of commercial automated systems, hydrogen / deuterium eXchange (HDX) is rapidly becoming the tool for mapping epitopes preferred by researchers in both industry and academia. However, this approach has a significant drawback in that it can be confounded by 'allosteric' structural and dynamic changes that result from the interaction, but occur far from the point(s) of contact...
September 21, 2017: MAbs
https://www.readbyqxmd.com/read/28931607/direct-observation-of-conformational-population-shifts-in-crystalline-human-hemoglobin
#2
Naoya Shibayama, Mio Ohki, Jeremy Rh Tame, Sam-Yong Park
Although X-ray crystallography is the most commonly used technique for studying the molecular structure of proteins, it is not generally able to monitor the dynamic changes or global domain motions that often underlie allostery. These motions often prevent crystal growth or reduce crystal order. We have recently discovered a crystal form of human hemoglobin that contains three protein molecules allowed to express a full range of quaternary structures, while maintaining strong X-ray diffraction. Here we use this crystal form to investigate the effects of two allosteric effectors, phosphate and bezafibrate, by tracking the structures and functions of the three hemoglobin molecules following the addition of each effector...
September 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28927275/proton-coupled-conformational-allostery-modulates-the-inhibitor-selectivity-for-%C3%AE-secretase
#3
Robert C Harris, Cheng-Chieh Tsai, Christopher R Ellis, Jana Shen
Many important pharmaceutical targets, such as aspartyl proteases and kinases, exhibit pH-dependent dynamics, functions and inhibition. Accurate prediction of their binding free energies is challenging because current computational techniques neglect the effects of pH. Here we combine free energy perturbation calculations with continuous constant pH molecular dynamics to explore the selectivity of a small-molecule inhibitor for β-secretase (BACE1), an important drug target for Alzheimer's disease. The calculations predicted identical affinity for BACE1 and the closely related cathepsin D at high pH; however, at pH 4...
September 21, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28917952/identification-of-potential-allosteric-communication-pathways-between-functional-sites-of-the-bacterial-ribosome-by-graph-and-elastic-network-models
#4
Pelin Guzel, Ozge Kurkcuoglu
BACKGROUND: Accumulated evidence indicates that bacterial ribosome employs allostery throughout its structure for protein synthesis. The nature of the allosteric communication between remote functional sites remains unclear, but the contact topology and dynamics of residues may play role in transmission of a perturbation to distant sites. METHODS/RESULTS: We employ two computationally efficient approaches - graph and elastic network modeling to gain insights about the allosteric communication in ribosome...
September 13, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28887304/allostery-between-two-binding-sites-in-the-ion-channel-subunit-trip8b-confers-binding-specificity-to-hcn-channels
#5
Kyle A Lyman, Ye Han, Robert J Heuermann, Xiangying Cheng, Jonathan E Kurz, Reagan E Lyman, Paul P Van Veldhoven, Dane M Chetkovich
Tetratricopeptide repeat (TPR) domains are ubiquitous structural motifs that mediate protein-protein interactions. For example, the TPR domains in the peroxisomal import receptor PEX5 enable binding to a range of type 1 peroxisomal targeting signal (PTS1) motifs. A homolog of PEX5, tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), binds to and functions as an auxiliary subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Given the similarity between TRIP8b and PEX5, this difference in function raises the question of what mechanism accounts for their binding specificity...
September 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28884867/uncovering-allostery-and-regulation-in-samhd1-through-molecular-dynamics-simulations
#6
Kajwal Kumar Patra, Akash Bhattacharya, Swati Bhattacharya
No abstract text is available yet for this article.
October 2017: Proteins
https://www.readbyqxmd.com/read/28882897/the-tiam1-guanine-nucleotide-exchange-factor-is-auto-inhibited-by-its-pleckstrin-homology-coiled-coil-extension-domain
#7
Zhen Xu, Lokesh Gakhar, Fletcher E Bain, Maria Spies, Ernesto J Fuentes
T-cell lymphoma invasion and metastasis 1 (Tiam1) is a Dbl-family guanine nucleotide exchange factor (GEF) that specifically activates the Rho-family GTPase Rac1 in response to upstream signals, thereby regulating cellular processes including cell adhesion and migration. Tiam1 contains multiple domains, including an N-terminal Pleckstrin homology coiled-coiled extension (PHn-CC-Ex) and catalytic Dbl-homology and C-terminal Pleckstrin homology (DH-PHc) domain. Previous studies indicate that larger fragments of Tiam1, such the region encompassing the N-terminal to C-terminal Pleckstrin homology domains (PHn-PHc) are auto-inhibited...
September 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28865247/allostery-in-enzyme-catalysis
#8
REVIEW
George P Lisi, J Patrick Loria
Modern interpretations of allostery typically rely on conformational ensembles to describe enzyme function. Conformational motions controlling these ensembles are often stimulated or quenched by allosteric effectors, and are critical to optimizing ligand binding pockets and enzyme architectures. Thus, enzymes rely on dynamic allosteric pathways that transmit long-range binding information to control catalysis. In this review, we provide a brief discussion of the ever-expanding principles of allosteric regulation in enzyme catalysis and highlight in-depth studies of three enzymes that have contributed to the paradigms of dynamic allostery...
August 30, 2017: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/28832583/deciphering-hla-i-motifs-across-hla-peptidomes-improves-neo-antigen-predictions-and-identifies-allostery-regulating-hla-specificity
#9
Michal Bassani-Sternberg, Chloé Chong, Philippe Guillaume, Marthe Solleder, HuiSong Pak, Philippe O Gannon, Lana E Kandalaft, George Coukos, David Gfeller
The precise identification of Human Leukocyte Antigen class I (HLA-I) binding motifs plays a central role in our ability to understand and predict (neo-)antigen presentation in infectious diseases and cancer. Here, by exploiting co-occurrence of HLA-I alleles across ten newly generated as well as forty public HLA peptidomics datasets comprising more than 115,000 unique peptides, we show that we can rapidly and accurately identify many HLA-I binding motifs and map them to their corresponding alleles without any a priori knowledge of HLA-I binding specificity...
August 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28820879/a-kinetic-view-of-gpcr-allostery-and-biased-agonism
#10
J Robert Lane, Lauren T May, Robert G Parton, Patrick M Sexton, Arthur Christopoulos
G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand-receptor and receptor-signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena...
August 18, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28819010/new-insight-on-the-s100a1-stip1-complex-highlights-the-important-relationship-between-allostery-and-entropy-in-protein-function
#11
REVIEW
Nathaniel V Nucci
Calcium signaling serves as a nexus of many vital cellular processes. Of particular importance is the role the calcium signaling plays in the prevention of protein misfolding, and the S100 family of calcium-binding proteins is a key player in this pathway. While the S100 proteins carry out a range of roles, the interaction of S100A1 and the stress-inducible phosphoprotein 1 (STIP1) has been shown to be particularly important. A recent study by Maciejewski et al. in Biochemical Journal (Biochemical Journal (2017) 474, 1853-1866) revealed new insights into the nature of the S100A1-STIP1 interaction...
August 17, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28813004/lactose-binding-induces-opposing-dynamics-changes-in-human-galectins-revealed-by-nmr-based-hydrogen-deuterium-exchange
#12
Chih-Ta Henry Chien, Meng-Ru Ho, Chung-Hung Lin, Shang-Te Danny Hsu
Galectins are β-galactoside-binding proteins implicated in a myriad of biological functions. Despite their highly conserved carbohydrate binding motifs with essentially identical structures, their affinities for lactose, a common galectin inhibitor, vary significantly. Here, we aimed to examine the molecular basis of differential lactose affinities amongst galectins using solution-based techniques. Consistent dissociation constants of lactose binding were derived from nuclear magnetic resonance (NMR) spectroscopy, intrinsic tryptophan fluorescence, isothermal titration calorimetry and bio-layer interferometry for human galectin-1 (hGal1), galectin-7 (hGal7), and the N-terminal and C-terminal domains of galectin-8 (hGal8(NTD) and hGal8(CTD), respectively)...
August 16, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28812955/igg-cooperativity-is-there-allostery-implications-for-antibody-functions-and-therapeutic-antibody-development
#13
Danlin Yang, Rachel Kroe-Barrett, Sanjaya Singh, Christopher J Roberts, Thomas M Laue
A central dogma in immunology is that an antibody's in vivo functionality is mediated by 2 independent events: antigen binding by the variable (V) region, followed by effector activation by the constant (C) region. However, this view has recently been challenged by reports suggesting allostery exists between the 2 regions, triggered by conformational changes or configurational differences. The possibility of allosteric signals propagating through the IgG domains complicates our understanding of the antibody structure-function relationship, and challenges the current subclass selection process in therapeutic antibody design...
August 16, 2017: MAbs
https://www.readbyqxmd.com/read/28809494/on-protein-assembly-and-building-blocks-beyond-the-limits-of-the-lego-bricks-metaphor
#14
Yaakov Levy
Proteins, similarly to other biomolecules, have a modular and hierarchical structure. Various building blocks serve to construct proteins of high structural complexity and diverse functionality. In multi-domain proteins, for example, domains are fused to each other in different combinations to achieve different functions. Although the LEGO bricks metaphor is justified as a means of simplifying the complexity of 3-dimensional protein structures, several fundamental properties (such as allostery or the induced-fit mechanism) make deviation from it necessary to respect the plasticity, softness, and cross-talks that are essential to protein function...
August 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/28808266/in-silico-analysis-of-glanzmann-variants-of-calf-1-domain-of-%C3%AE-iib%C3%AE-3-integrin-revealed-dynamic-allosteric-effect
#15
Matthieu Goguet, Tarun Jairaj Narwani, Rachel Petermann, Vincent Jallu, Alexandre G de Brevern
Integrin αIIbβ3 mediates platelet aggregation and thrombus formation. In a rare hereditary bleeding disorder, Glanzmann thrombasthenia (GT), αIIbβ3 expression / function are impaired. The impact of deleterious missense mutations on the complex structure remains unclear. Long independent molecular dynamics (MD) simulations were performed for 7 GT variants and reference structure of the Calf-1 domain of αIIb. Simulations were analysed using a structural alphabet to describe local protein conformations. Common and flexible regions as well as deformable zones were observed in all the structures...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28808063/phylogenetic-sequence-analysis-and-functional-studies-reveal-compensatory-amino-acid-substitutions-in-loop-2-of-human-ribonucleotide-reductase
#16
Andrew J Knappenberger, Sneha Grandhi, Reena Sheth, Md Faiz Ahmad, Rajesh Viswanathan, Michael E Harris
Eukaryotic class I ribonucleotide reductases (RRs) generate deoxyribonucleotides for DNA synthesis. Binding of dNTP effectors is coupled to the formation of active dimers and induces conformational changes in a short loop (loop 2) to regulate RR's specificity among its nucleoside diphosphate (NDP) substrates. Moreover, ATP and dATP bind at an additional allosteric site 40 Å away from loop 2 and thereby drive formation of activated or inactive hexamers, respectively. To better understand how dNTP binding influences specificity, activity, and oligomerization of human RR, we aligned >300 eukaryotic RR sequences to examine natural sequence variation in loop 2...
August 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28807238/unravelling-the-complexity-of-signalling-networks-in-cancer-a-review-of-the-increasing-role-for-computational-modelling
#17
REVIEW
John Garland
Cancer induction is a highly complex process involving hundreds of different inducers but whose eventual outcome is the same. Clearly, it is essential to understand how signalling pathways and networks generated by these inducers interact to regulate cell behaviour and create the cancer phenotype. While enormous strides have been made in identifying key networking profiles, the amount of data generated far exceeds our ability to understand how it all "fits together". The number of potential interactions is astronomically large and requires novel approaches and extreme computation methods to dissect them out...
September 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28807050/cooperative-binding-mitigates-the-high-dose-hook-effect
#18
Ranjita Dutta Roy, Christian Rosenmund, Melanie I Stefan
BACKGROUND: The high-dose hook effect (also called prozone effect) refers to the observation that if a multivalent protein acts as a linker between two parts of a protein complex, then increasing the amount of linker protein in the mixture does not always increase the amount of fully formed complex. On the contrary, at a high enough concentration range the amount of fully formed complex actually decreases. It has been observed that allosterically regulated proteins seem less susceptible to this effect...
August 14, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28805377/intrinsic-dynamics-of-the-binding-rail-and-its-allosteric-effect-in-the-class-i-histone-deacetylases
#19
Jingwei Zhou, Yue Huang, Chunyan Cheng, Kai Wang, Ruibo Wu
The development of novel isoform/class-selective inhibitors is still of great biological and medical significance to conquer the continuously reported side effects for the histone deacetylase (HDAC) drugs. The first potent HDAC allosteric inhibitor was discovered last year, and this allosteric inhibitor design is thought to be a promising strategy to overcome the current challenges in HDAC inhibitor design. However, the detailed allosteric mechanism and its remote regulatory effects on the catalytic/inhibitor activity of HDAC are still unclear...
August 25, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28805060/substrate-induced-facilitated-dissociation-of-the-competitive-inhibitor-from-the-active-site-of-o-acetyl-serine-sulfhydrylase-reveals-a-competitive-allostery-mechanism
#20
Appu Kumar Singh, Mary Krishna Ekka, Abhishek Kaushik, Vaibhav Pandya, Ravi P Singh, Shrijita Banerjee, Monica Mittal, Vijay Singh, S Kumaran
By classical competitive antagonism, a substrate and competitive inhibitor must bind mutually exclusively to the active site. The competitive inhibition of O-acetyl serine sulfhydrylase (OASS) by the C-terminus of serine acetyltransferase (SAT) presents a paradox, because the C-terminus of SAT binds to the active site of OASS with an affinity that is 4-6 log-fold (10(4)-10(6)) greater than that of the substrate. Therefore, we employed multiple approaches to understand how the substrate gains access to the OASS active site under physiological conditions...
September 1, 2017: Biochemistry
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