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https://www.readbyqxmd.com/read/28718281/long-distance-modulation-of-disorder-to-order-in-protein-allostery
#1
Jingheng Wang, Gregory S 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 E. coli biotin repressor, BirA, is allosterically activated by binding of the small molecule effector biotinoyl-5'-AMP...
July 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28716627/membrane-proteins-structures-a-review-on-computational-modeling-tools
#2
REVIEW
Jose G Almeida, Antonio J Preto, Panagiotis I Koukos, Alexandre M J J Bonvin, Irina S Moreira
BACKGROUND: Membrane proteins (MPs) play diverse and important functions in living organisms. They constitute 20% to 30% of the known bacterial, archaean and eukaryotic organisms' genomes. In humans, their importance is emphasized as they represent 50% of all known drug targets. Nevertheless, experimental determination of their three-dimensional (3D) structure has proven to be both time consuming and rather expensive, which has led to the development of computational algorithms to complement the available experimental methods and provide valuable insights...
July 15, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28710372/phthalide-derivatives-from-angelica-sinensis-decrease-hemoglobin-oxygen-affinity-a-new-allosteric-modulating-mechanism-and-potential-use-as-2-3-bpg-functional-substitutes
#3
Wei-Ren Chen, Youqing Yu, Muhammad Zulfajri, Ping-Cheng Lin, Chia C Wang
Angelica sinensis (AS), one of the most versatile herbal medicines remains widely used due to its multi-faceted pharmacologic activities. Besides its traditional use as the blood-nourishing tonic, its anti-hypertensive, anti-cardiovascular, neuroprotective and anti-cancer effects have been reported. Albeit the significant therapeutic effects, how AS exerts such diverse efficacies from the molecular level remains elusive. Here we investigate the influences of AS and four representative phthalide derivatives from AS on the structure and function of hemoglobin (Hb)...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28701416/eukaryotic-transcription-factors-paradigms-of-protein-intrinsic-disorder
#4
REVIEW
Lasse Staby, Charlotte O'Shea, Martin Willemoës, Frederik Theisen, Birthe B Kragelund, Karen Skriver
Gene-specific transcription factors (TFs) are key regulatory components of signaling pathways, controlling, for example, cell growth, development, and stress responses. Their biological functions are determined by their molecular structures, as exemplified by their structured DNA-binding domains targeting specific cis-acting elements in genes, and by the significant lack of fixed tertiary structure in their extensive intrinsically disordered regions. Recent research in protein intrinsic disorder (ID) has changed our understanding of transcriptional activation domains from 'negative noodles' to ID regions with function-related, short sequence motifs and molecular recognition features with structural propensities...
July 12, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28700571/open-and-closed-structures-reveal-allostery-and-pliability-in-the-hiv-1-envelope-spike
#5
Gabriel Ozorowski, Jesper Pallesen, Natalia de Val, Dmitry Lyumkis, Christopher A Cottrell, Jonathan L Torres, Jeffrey Copps, Robyn L Stanfield, Albert Cupo, Pavel Pugach, John P Moore, Ian A Wilson, Andrew B Ward
For many enveloped viruses, binding to a receptor(s) on a host cell acts as the first step in a series of events culminating in fusion with the host cell membrane and transfer of genetic material for replication. The envelope glycoprotein (Env) trimer on the surface of HIV is responsible for receptor binding and fusion. Although Env can tolerate a high degree of mutation in five variable regions (V1-V5), and also at N-linked glycosylation sites that contribute roughly half the mass of Env, the functional sites for recognition of receptor CD4 and co-receptor CXCR4/CCR5 are conserved and essential for viral fitness...
July 12, 2017: Nature
https://www.readbyqxmd.com/read/28696318/energetic-redistribution-in-allostery-to-execute-protein-function
#6
Jin Liu, Ruth Nussinov
No abstract text is available yet for this article.
July 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28694495/functional-determinants-of-protein-assembly-into-homomeric-complexes
#7
L Therese Bergendahl, Joseph A Marsh
Approximately half of proteins with experimentally determined structures can interact with other copies of themselves and assemble into homomeric complexes, the overwhelming majority of which (>96%) are symmetric. Although homomerisation is often assumed to a functionally beneficial result of evolutionary selection, there has been little systematic analysis of the relationship between homomer structure and function. Here, utilizing the large numbers of structures and functional annotations now available, we have investigated how proteins that assemble into different types of homomers are associated with different biological functions...
July 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28691825/small-molecule-recognition-triggers-secondary-and-tertiary-interactions-in-dna-folding-and-hammerhead-ribozyme-catalysis
#8
Jie Mao, Chris DeSantis, Dennis Bong
We have identified tris(2-aminoethyl)amine (tren)-derived scaffolds with two (t2M) or four (t4M) melamine rings that can target oligo T/U domains in DNA/RNA. Unstructured T-rich DNAs cooperatively fold with the tren derivatives to form hairpin-like structures. Both t2M and t4M act as functional switches in a family of hammerhead ribozymes deactivated by stem or loop replacement with a U-rich sequence. Catalysis of bond scission in these hammerhead ribozymes could be restored by putative t2M/t4M refolding of stem secondary structure or tertiary bridging interactions between loop and stem...
July 13, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28668119/dna-pkcs-allostery-and-dna-double-strand-break-repair-defining-the-structure-and-setting-the-stage
#9
Dimitri Y Chirgadze, David B Ascher, Tom L Blundell, Bancinyane L Sibanda
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is central to the regulation of the DNA damage response and repair through nonhomologous end joining. The structure has proved challenging due to its large size and multiple HEAT repeats. We have recently reported crystals of selenomethionine-labeled DNA-PKcs complexed with native KU80ct194 (KU80 residues 539-732) diffracting to 4.3Å resolution. The novel use of crystals of selenomethionine-labeled protein expressed in HeLa cells has facilitated the use of single anomalous X-ray scattering of this 4128 amino acid, multiple HEAT-repeat structure...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28661652/human-concentrative-nucleoside-transporter-3-hcnt3-slc28a3-forms-a-cyclic-homotrimer
#10
Adrian Stecula, Avner Schlessinger, Kathleen M Giacomini, Andrej Sali
Many anticancer and antiviral drugs are purine or pyrimidine analogues, which use membrane transporters to cross cellular membranes. Concentrative nucleoside transporters (CNTs) mediate the salvage of nucleosides and the transport of therapeutic nucleoside analogues across plasma membranes by coupling the transport of ligands to the sodium gradient. Of the three members of the human CNT family, CNT3 has the broadest selectivity and the widest expression profile. However, the molecular mechanisms of the transporter, including how it interacts with and translocates structurally diverse nucleosides and nucleoside analogues, are unclear...
June 29, 2017: Biochemistry
https://www.readbyqxmd.com/read/28634294/hidden-electrostatic-basis-of-dynamic-allostery-in-a-pdz-domain
#11
Amit Kumawat, Suman Chakrabarty
Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to the traditionally used structure-based parameters...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28617332/dynamic-allostery-modulates-catalytic-activity-by-modifying-the-hydrogen-bonding-network-in-the-catalytic-site-of-human-pin1
#12
Jing Wang, Ryosuke Kawasaki, Jun-Ichi Uewaki, Arif U R Rashid, Naoya Tochio, Shin-Ichi Tate
Allosteric communication among domains in modular proteins consisting of flexibly linked domains with complimentary roles remains poorly understood. To understand how complementary domains communicate, we have studied human Pin1, a representative modular protein with two domains mutually tethered by a flexible linker: a WW domain for substrate recognition and a peptidyl-prolyl isomerase (PPIase) domain. Previous studies of Pin1 showed that physical contact between the domains causes dynamic allostery by reducing conformation dynamics in the catalytic domain, which compensates for the entropy costs of substrate binding to the catalytic site and thus increases catalytic activity...
June 15, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28598329/glycolytic-reliance-promotes-anabolism-in-photoreceptors
#13
Yashodhan Chinchore, Tedi Begaj, David Wu, Eugene Drokhlyansky, Constance L Cepko
Vertebrate photoreceptors are among the most metabolically active cells, exhibiting a high rate of ATP consumption. This is coupled with a high anabolic demand, necessitated by the diurnal turnover of a specialized membrane-rich organelle, the outer segment, which is the primary site of phototransduction. How photoreceptors balance their catabolic and anabolic demands is poorly understood. Here, we show that rod photoreceptors in mice rely on glycolysis for their outer segment biogenesis. Genetic perturbations targeting allostery or key regulatory nodes in the glycolytic pathway impacted the size of the outer segments...
June 9, 2017: ELife
https://www.readbyqxmd.com/read/28593140/dna-induced-unfolding-of-the-thyroid-hormone-receptor-%C3%AE-a-b-domain-through-allostery
#14
Elias J Fernandez, Vandna Gahlot, Celeste Rodriguez, Jacob Amburn
The A/B domains of nuclear receptors such as thyroid receptor α (TRα) are considered to be conformationally flexible and can potentially adopt multiple structural conformations. We used intrinsic tryptophan fluorescence quenching and circular dichroism spectroscopy to characterize the unfolding of this A/B domain upon DNA binding to the contiguous DNA-binding domain (DBD). We propose that this allosteric change in A/B domain conformation can allow it to make the multiple interactions with distinct molecular factors of the transcriptional preinitiation complex...
June 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28548177/specific-dna-sequences-allosterically-enhance-protein-protein-interaction-in-a-transcription-factor-through-modulation-of-protein-dynamics-implications-for-specificity-of-gene-regulation
#15
Abhishek Mazumder, Subrata Batabyal, Manas Mondal, Tanumoy Mondol, Susobhan Choudhury, Raka Ghosh, Tanaya Chatterjee, Dhananjay Bhattacharyya, Samir Kumar Pal, Siddhartha Roy
Most genes are regulated by multiple transcription factors, often assembling into multi-protein complexes in the gene regulatory region. Understanding of the molecular origin of specificity of gene regulatory complex formation in the context of the whole genome is currently inadequate. A phage transcription factor λ-CI forms repressive multi-protein complexes by binding to multiple binding sites in the genome to regulate the lifecycle of the phage. The protein-protein interaction between two DNA-bound λ-CI molecules is stronger when they are bound to the correct pair of binding sites, suggesting allosteric transmission of recognition of correct DNA sequences to the protein-protein interaction interface...
June 7, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28546419/direct-binding-of-the-corrector-vx-809-to-human-cftr-nbd1-evidence-of-an-allosteric-coupling-between-the-binding-site-and-the-nbd1-cl4-interface
#16
Rhea P Hudson, Jennifer E Dawson, P Andrew Chong, Zhengrong Yang, Linda Millen, Philip J Thomas, Christie G Brouillette, Julie D Forman-Kay
Understanding the mechanism of action of modulator compounds for the cystic fibrosis transmembrane conductance regulator (CFTR) is key for optimization of therapeutics as well as obtaining insights into the molecular mechanisms of CFTR function. We demonstrate direct binding of VX-809 to the first nucleotide-binding domain (NBD1) of human CFTR. Disruption of the interaction between C-terminal helices and the NBD1 core upon VX-809 binding is observed from chemical shift changes in the NMR spectra of residues in the helices and on the surface of β-strands S3, S9 and S10...
May 25, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28537745/deciphering-cryptic-binding-sites-on-proteins-by-mixed-solvent-molecular-dynamics
#17
S Roy Kimura, Hai Peng Hu, Anatoly M Ruvinsky, Woody Sherman, Angelo D Favia
In recent years, molecular dynamics simulations of proteins in explicit mixed solvents have been applied to various problems in protein biophysics and drug discovery, including protein folding, protein surface characterization, fragment screening, allostery, and druggability assessment. In this study, we perform a systematic study on how mixtures of organic solvent probes in water can reveal cryptic ligand binding pockets that are not evident in crystal structures of apo proteins. We examine a diverse set of eight PDB proteins that show pocket opening induced by ligand binding and investigate whether solvent MD simulations on the apo structures can induce the binding site observed in the holo structures...
June 8, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28532213/what-do-structures-tell-us-about-chemokine-receptor-function-and-antagonism
#18
Irina Kufareva, Martin Gustavsson, Yi Zheng, Bryan S Stephens, Tracy M Handel
Chemokines and their cell surface G protein-coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs...
May 22, 2017: Annual Review of Biophysics
https://www.readbyqxmd.com/read/28522638/a-self-consistent-structural-perturbation-approach-for-determining-the-magnitude-and-extent-of-allosteric-coupling-in-proteins
#19
Nandakumar Rajasekaran, Athi N Naganathan
Elucidating the extent of energetic coupling between residues in single-domain proteins, a fundamental determinant of allostery, information transfer and folding cooperativity, has remained a grand challenge. While several sequence- and structure-based approaches have been proposed, a self-consistent description that is simultaneously compatible with unfolding thermodynamics is lacking. We had recently developed a simple structural perturbation protocol that captures the changes in thermodynamic stabilities induced by point mutations within the protein interior...
May 18, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28507717/dynamic-structural-and-thermodynamic-basis-of-insulin-like-growth-factor-1-kinase-allostery-mediated-by-activation-loop-phosphorylation
#20
Yaozong Li, Kwangho Nam
Despite the importance of kinases' catalytic activity regulation in cell signaling, detailed mechanisms underlying their activity regulation are poorly understood. Herein, using insulin-like growth factor 1 receptor kinase (IGF-1RK) as a model, the mechanisms of kinase regulation by its activation loop (A-loop) phosphorylation were investigated through molecular dynamics (MD) and alchemical free energy simulations. Analyses of the simulation results and free energy landscapes determined for the entire catalytic cycle of the kinase revealed that A-loop phosphorylation affects each step in the IGF-1RK catalytic cycle, including conformational change, substrate binding/product release and catalytic phosphoryl transfer...
May 1, 2017: Chemical Science
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