scholarly journals Role of the histone amino termini in facilitated binding of a transcription factor, GAL4-AH, to nucleosome cores.

1994 ◽  
Vol 14 (2) ◽  
pp. 970-981 ◽  
Author(s):  
M Vettese-Dadey ◽  
P Walter ◽  
H Chen ◽  
L J Juan ◽  
J L Workman
Keyword(s):  
Dna Binding ◽  
Binding Sites ◽  
Core Histone ◽  
Nucleosome Core ◽  
Naked Dna ◽  
The Core ◽  
Nucleosomal Dna ◽  
Multiple Binding Sites ◽  
Multiple Binding

Facilitated, "cooperative" binding of GAL4-AH to nucleosomal DNA occurred in response to inhibition from the core histone amino termini. The binding of GAL4-AH (which contains the DNA-binding and dimerization domains of GAL4) to nucleosome cores containing multiple binding sites initiated at the end of a nucleosome core and proceeded in a cooperative manner until all sites were occupied. However, following tryptic removal of the core histone amino termini, GAL4-AH binding appeared to be noncooperative, similar to binding naked DNA. Binding of GAL4-AH to nucleosomes bearing a single GAL4 site at different positions indicated that inhibition of GAL4 binding was largely mediated by the histone amino termini and primarily occurred at sites well within the core and not near the end. When the histone amino termini were intact, binding of GAL4-AH to sites near the center of a nucleosome core was greatly enhanced by the presence of additional GAL4 dimers bound to more-accessible positions. These data illustrate that the binding of a factor to more-accessible sites, near the end of a nucleosome, allows facilitated binding of additional factors to the center of the nucleosome, thereby overcoming repression from the core histone amino termini. This mechanism may contribute to the binding of multiple factors to complex promoter and enhancer elements in cellular chromatin.

The role of multiple binding sites in the activation of zein gene expression byOpaque-2

1996 ◽  
Vol 252 (6) ◽  
pp. 723-732 ◽  
Author(s):  
J. R. Muth ◽  
M. Müller ◽  
S. Lohmer ◽  
F. Salamini ◽  
R. D. Thompson
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Zein Gene

The role of multiple binding sites in the activation of zein gene expression by

1996 ◽  
Vol 252 (6) ◽  
pp. 723 ◽  
Author(s):  
Jost R. Muth ◽  
Martin Müller ◽  
S. Lohmer ◽  
Francesco Salamini ◽  
R. D. Thompson
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Zein Gene

Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels

2020 ◽  
Vol 60 (1) ◽  
pp. 219-240 ◽  
Author(s):  
Brandon M. Brown ◽  
Heesung Shim ◽  
Palle Christophersen ◽  
Heike Wulff
Keyword(s):  
Small Molecule ◽  
Binding Sites ◽  
Physiological Role ◽  
Membrane Hyperpolarization ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Calcium Activated Potassium Channels ◽  
Small Conductance ◽  
Made In

The three small-conductance calcium-activated potassium (KCa2) channels and the related intermediate-conductance KCa3.1 channel are voltage-independent K+ channels that mediate calcium-induced membrane hyperpolarization. When intracellular calcium increases in the channel vicinity, it calcifies the flexible N lobe of the channel-bound calmodulin, which then swings over to the S4-S5 linker and opens the channel. KCa2 and KCa3.1 channels are highly druggable and offer multiple binding sites for venom peptides and small-molecule blockers as well as for positive- and negative-gating modulators. In this review, we briefly summarize the physiological role of KCa channels and then discuss the pharmacophores and the mechanism of action of the most commonly used peptidic and small-molecule KCa2 and KCa3.1 modulators. Finally, we describe the progress that has been made in advancing KCa3.1 blockers and KCa2.2 negative- and positive-gating modulators toward the clinic for neurological and cardiovascular diseases and discuss the remaining challenges.

scholarly journals Binding of heparin to human thyroglobulin (Tg) involves multiple binding sites including a region corresponding to a binding site of rat Tg

2002 ◽  
pp. 591-602 ◽  
Author(s):  
S Lisi ◽  
A Pinchera ◽  
RT McCluskey ◽  
L Chiovato ◽  
M Marino
Keyword(s):  
Binding Sites ◽  
Solid Phase ◽  
Heparin Binding ◽  
Binding Ability ◽  
Lower Affinity ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Lower Extent ◽  
Dose Dependent

OBJECTIVE: Binding of thyroglobulin (Tg) to heparin allows efficient Tg interaction with its endocytic receptor, megalin. Rat Tg (rTg) binds to heparin using an exposed carboxyl terminal region (RELPSRRLKRPLPVK, Arg2489-Lys2503) rich in positively charged residues which is, however, not entirely conserved in human Tg (hTg) (Arg2489-Glu2503, REPPARALKRSLWVE). Here, we investigated whether and how this difference affects binding of heparin. DESIGN: To compare binding of heparin to rTg and hTg. To investigate the role of the sequence 2489-2503 using a peptide-based approach. METHODS: Binding of biotin-labeled heparin to rTg, hTg and to Tg peptides was measured in solid phase assays. RESULTS: Heparin bound to rTg with moderately high affinity (K(d): 34.2 nmol/l, K(i): 37.6 nmol/l) and to hTg with lower affinity (K(d): 118 nmol/l, K(i): 480 nmol/l) and to a lower extent. Binding was dose-dependent and saturable, and was reduced by several specific competitors (Tg itself, unlabeled heparin, lactoferrin). Heparin bound to synthetic peptides corresponding to the rat (rTgP) and to the human (hTgP) Tg sequence 2489-2503. Heparin bound to rTgP to a greater extent and with greater affinity than to hTgP. An antibody against hTgP reduced binding of heparin to intact hTg by 30%, suggesting that in hTg this region is, in part, involved in heparin binding, but also that other regions account for most of the binding. Starting from the sequence of rTgP, we designed 6 synthetic 'mutant' peptides by replacing one amino acid residue of rTgP with the corresponding residue of the sequence of hTgP. Heparin bound to 5 of 6 mutant peptides to a lower extent and with lower affinity than to rTgP. CONCLUSIONS: In spite of a reduced binding ability of the sequence 2489-2503, hTg binds to heparin, in part, using alternative, as yet unidentified, binding sites. Substitution of both positive and neutral residues within the sequence 2489-2503 reduced heparin-binding, suggesting that not only charge, but also sequence and/or conformation, may account for the heparin-binding ability of this region of Tg.

Iron binding to human heavy-chain ferritin

2015 ◽  
Vol 71 (9) ◽  
pp. 1909-1920 ◽  
Author(s):  
Cecilia Pozzi ◽  
Flavio Di Pisa ◽  
Caterina Bernacchioni ◽  
Silvia Ciambellotti ◽  
Paola Turano ◽  
...  
Keyword(s):  
Binding Sites ◽  
Rana Catesbeiana ◽  
Storage Proteins ◽  
Similar Data ◽  
Iron Binding ◽  
Iron Storage ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Iron Storage Proteins

Maxi-ferritins are ubiquitous iron-storage proteins with a common cage architecture made up of 24 identical subunits of five α-helices that drive iron biomineralization through catalytic iron(II) oxidation occurring at oxidoreductase sites (OS). Structures of iron-bound human H ferritin were solved at high resolution by freezing ferritin crystals at different time intervals after exposure to a ferrous salt. Multiple binding sites were identified that define the iron path from the entry ion channels to the oxidoreductase sites. Similar data are available for another vertebrate ferritin: the M protein fromRana catesbeiana. A comparative analysis of the iron sites in the two proteins identifies new reaction intermediates and underlines clear differences in the pattern of ligands that define the additional iron sites that precede the oxidoreductase binding sites along this path. Stopped-flow kinetics assays revealed that human H ferritin has different levels of activity compared with itsR. catesbeianacounterpart. The role of the different pattern of transient iron-binding sites in the OS is discussed with respect to the observed differences in activity across the species.

NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites

2019 ◽  
Vol 19 (24) ◽  
pp. 2239-2253 ◽  
Author(s):  
Paul J. Goldsmith
Keyword(s):  
Binding Sites ◽  
Receptor Activation ◽  
Research Area ◽  
Allosteric Modulators ◽  
Nonselective Cation Channels ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Excitatory Neurotransmission ◽  
Psychiatric Conditions ◽  
High Level

The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.

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