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https://www.readbyqxmd.com/read/28813004/lactose-binding-induces-opposing-dynamics-changes-in-human-galectins-revealed-by-nmr-based-hydrogen-deuterium-exchange
#1
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
#2
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 two 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 two 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
#3
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
#4
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
#5
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
#6
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
#7
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-binding-rail-and-its-allosteric-effect-in-the-class-i-hdacs
#8
Jingwei Zhou, Yue Huang, Chunyan Cheng, Kai Wang, Ruibo Wu
The development of novel isoform/class-selective inhibitor is still of great biological and medical significance to conquer the continuously reported side effects for the histone deacetylases (HDACs) 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 mechanisms and its remote regulation effects on the catalytic/inhibitor activity of HDAC are still unclear...
August 14, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28805060/substrate-induced-facilitated-dissociation-of-competitive-inhibitor-from-the-active-site-of-o-acetyl-serine-sulfhydrylase-reveal-a-competitive-allostery-mechanism
#9
Appu Kumar Singh, Mary Krishna Ekka, Abhishek Kaushik, Vaibhav Kumar Pandya, Ravi Pratap Singh, Srijita Banerjee, Monica Mittal, Vijay Singh, Sangaralingam Kumaran
By classical competitive-antagonism, substrate and competitive-inhibitor must bind mutually exclusively to the active site. The competitive inhibition of O-acetyl serine sulfhydrylase (OASS) by C-terminal of serine acetyltransferase (SAT) presents a paradox, because the C-terminal of SAT binds to the active site of OASS with 4-6 log fold (104 -106) more affinity than that of the substrate. Therefore, we employed multiple approaches to understand how substrate gains access to OASS active site under physiological conditions...
August 14, 2017: Biochemistry
https://www.readbyqxmd.com/read/28793329/using-the-mwc-model-to-describe-heterotropic-interactions-in-hemoglobin
#10
Olga Rapp, Ofer Yifrach
Hemoglobin is a classical model allosteric protein. Research on hemoglobin parallels the development of key cooperativity and allostery concepts, such as the 'all-or-none' Hill formalism, the stepwise Adair binding formulation and the concerted Monod-Wymann-Changuex (MWC) allosteric model. While it is clear that the MWC model adequately describes the cooperative binding of oxygen to hemoglobin, rationalizing the effects of H+, CO2 or organophosphate ligands on hemoglobin-oxygen saturation using the same model remains controversial...
2017: PloS One
https://www.readbyqxmd.com/read/28793211/design-of-elastic-networks-with-evolutionary-optimized-long-range-communication-as-mechanical-models-of-allosteric-proteins
#11
Holger Flechsig
Allosteric effects often underlie the activity of proteins, and elucidating generic design aspects and functional principles unique to allosteric phenomena represent a major challenge. Here an approach consisting of the in silico design of synthetic structures, which, as the principal element of allostery, encode dynamical long-range coupling among two sites, is presented. The structures are represented by elastic networks, similar to coarse-grained models of real proteins. A strategy of evolutionary optimization was implemented to iteratively improve allosteric coupling...
August 8, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28771551/computational-investigation-of-conformational-variability-and-allostery-in-cathepsin-k-and-other-related-peptidases
#12
Marko Novinec
Allosteric targeting is progressively gaining ground as a strategy in drug design. Its success, however, depends on our knowledge of the investigated system. In the case of the papain-like cysteine peptidase cathepsin K, a major obstacle in our understanding of allostery is represented by the lack of observable conformational change at the active site. This makes it difficult to understand how binding of effectors at known allosteric sites translates into modified enzyme activity. Herein, we address this issue by a computational approach based on experimental data...
2017: PloS One
https://www.readbyqxmd.com/read/28768808/transmembrane-allosteric-energetics-characterization-for-strong-coupling-between-proton-and-potassium-ion-binding-in-the-kcsa-channel
#13
Yunyao Xu, Manasi P Bhate, Ann E McDermott
The slow spontaneous inactivation of potassium channels exhibits classic signatures of transmembrane allostery. A variety of data support a model in which the loss of K(+) ions from the selectivity filter is a major factor in promoting inactivation, which defeats transmission, and is allosterically coupled to protonation of key channel activation residues, more than 30 Å from the K(+) ion binding site. We show that proton binding at the intracellular pH sensor perturbs the potassium affinity at the extracellular selectivity filter by more than three orders of magnitude for the full-length wild-type KcsA, a pH-gated bacterial channel, in membrane bilayers...
August 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28764328/protospacer-adjacent-motif-induced-allostery-activates-crispr-cas9
#14
Giulia Palermo, Clarisse G Ricci, Amendra Fernando, Rajshekhar Basak, Martin Jinek, Ivan Rivalta, Victor S Batista, J Andrew McCammon
CRISPR-Cas9 is a genome editing technology with major impact in life sciences. In this system, the endonuclease Cas9 generates double strand breaks in DNA upon RNA-guided recognition of a complementary DNA sequence, which strictly requires the presence of a protospacer adjacent motif (PAM) next to the target site. Although PAM recognition is essential for cleavage, it is unknown whether and how PAM binding activates Cas9 for DNA cleavage at spatially distant sites. Here, we find evidence of a PAM-induced allosteric mechanism revealed by microsecond molecular dynamics simulations...
August 7, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28760989/time-resolved-observation-of-protein-allosteric-communication
#15
Sebastian Buchenberg, Florian Sittel, Gerhard Stock
Allostery represents a fundamental mechanism of biological regulation that is mediated via long-range communication between distant protein sites. Although little is known about the underlying dynamical process, recent time-resolved infrared spectroscopy experiments on a photoswitchable PDZ domain (PDZ2S) have indicated that the allosteric transition occurs on multiple timescales. Here, using extensive nonequilibrium molecular dynamics simulations, a time-dependent picture of the allosteric communication in PDZ2S is developed...
August 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28754691/the-hsp70-interdomain-linker-is-a-dynamic-switch-that-enables-allosteric-communication-between-two-structured-domains
#16
Charles A English, Woody Sherman, Wenli Meng, Lila M Gierasch
Hsp70 molecular chaperones play key roles in cellular protein homeostasis by binding to exposed hydrophobic regions of incompletely folded or aggregated proteins. This crucial Hsp70 function relies on allosteric communication between two well-structured domains: an N-terminal nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain (SBD), which are tethered by an interdomain linker. ATP or ADP binding to the NBD alters the substrate-binding affinity of the SBD, triggering functionally essential cycles of substrate binding and release...
July 28, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28741612/an-information-theoretic-framework-reveals-a-tunable-allosteric-network-in-group-ii-chaperonins
#17
Tom Lopez, Kevin Dalton, Anthony Tomlinson, Vijay Pande, Judith Frydman
ATP-dependent allosteric regulation of the ring-shaped group II chaperonins remains ill defined, in part because their complex oligomeric topology has limited the success of structural techniques in suggesting allosteric determinants. Further, their high sequence conservation has hindered the prediction of allosteric networks using mathematical covariation approaches. Here, we develop an information theoretic strategy that is robust to residue conservation and apply it to group II chaperonins. We identify a contiguous network of covarying residues that connects all nucleotide-binding pockets within each chaperonin ring...
July 24, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28739805/functional-insights-into-the-mode-of-dna-and-ligand-binding-of-the-tetr-family-regulator-tylp-from-streptomyces-fradiae
#18
Shamayeeta Ray, Anwesha Maitra, Anwesha Biswas, Santosh Panjikar, Jagannath Mondal, Ruchi Anand
Tetracycline Repressors (TetRs) modulate multi-drug efflux pathways in several pathogenic bacteria. In Streptomyces, they additionally regulate secondary metabolic pathways like antibiotic production. For instance, in the antibiotic producer Streptomyces fradiae, a layered network of TetRs regulate the levels of commercially important antibiotic tylosin, with TylP occupying the top of this cascading network. TetRs exist in two functional states; the DNA-bound and the ligand-bound form, which are allosterically regulated...
July 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28738682/prototropically-allosteric-probe-for-superbly-selective-dna-analysis
#19
Fan Lin, Yufeng Zhou, Qiusha Li, Xiaoshun Zhou, Yong Shao, Benoit Habermeyer, Hui Wang, Xinghua Shi, Zhiai Xu
Selective nucleotide recognition for biosensor evolution requires rational probe design toward the binding-pattern-susceptible readout but without serious poison in selectivity from the context sequences. In this work, we synthesized a dual-function (trihydroxyphenyl)porphyrin (POH3) to target the abasic site (AP site) in ds-DNA using the trihydroxyphenyl substituent and the tetrapyrrole macrocycle as the recognition unit (RU) and the fluorescent signal unit (SU), respectively. RU and SU are separated from each other but are prototropically allosteric...
August 11, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28718281/long-distance-modulation-of-disorder-to-order-transitions-in-protein-allostery
#20
Jingheng Wang, Gregory Custer, Dorothy Beckett, Silvina Matysiak
Elucidation of the molecular details of allosteric communication between distant sites in a protein is key to understanding and manipulating many biological regulatory processes. Although protein disorder is acknowledged to play an important thermodynamic role in allostery, the molecular mechanisms by which this disorder is harnessed for long distance communication are known for a limited number of systems. Transcription repression by the Escherichia coli biotin repressor, BirA, is allosterically activated by binding of the small molecule effector biotinoyl-5'-AMP...
August 14, 2017: Biochemistry
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