Anion binding modes in cis–trans-isomers of a binding site–fluorophore–π-extended system

2014 ◽  
Vol 50 (94) ◽  
pp. 14748-14751 ◽  
Author(s):  
Min Zhou ◽  
Jinju Chen ◽  
Chuanxiang Liu ◽  
Hanghai Fu ◽  
Nan Zheng ◽  
...  
Keyword(s):  
Binding Site ◽  
Anion Binding ◽  
Binding Modes ◽  
Trans Isomers ◽  
Extended System ◽  
In Cis

scholarly journals Plasmodium falciparum DHODH inhibitor complexes reveal flexible binding site

2014 ◽  
Vol 70 (a1) ◽  
pp. C1793-C1793
Author(s):  
Paul Rowland ◽  
Onkar SINGH ◽  
Leila Ross ◽  
Francisco Gamo ◽  
Maria Lafuente-Monasterio ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Binding Site ◽  
Crystal Structures ◽  
Point Mutations ◽  
Crystal Form ◽  
Drug Binding ◽  
Binding Modes ◽  
Resistance Mutations ◽  
Drug Binding Site

Malaria is a preventable and treatable disease, yet annually there are still hundreds of thousands of malaria-related deaths. The disease is caused by infection with mosquito-borne Plasmodium parasites. With hundreds of millions of cases each year there is a very high potential for drug resistance and this has compromised many existing therapies. One target under investigation is the enzyme dihydroorotate dehydrogenase (DHODH) which catalyses the rate-limiting step of pyrimidine biosynthesis and is an essential enzyme in the malaria parasite. There are currently several Plasmodium-selective DHODH inhibitors under development. To investigate the potential for drug resistance against DHODH inhibitors in vitro resistance selections were carried out using known inhibitors from different structural classes [1]. These studies identified point mutations in the drug binding site which lead to reduced sensitivity to the inhibitors, and in some cases increased sensitivity to a different inhibitor, suggesting a novel combination therapy approach to combat resistance. To help understand the significance of the inhibitor binding site mutations we determined the crystal structures of P. falciparum DHODH in complex with the inhibitors Genz-669178, IDI-6253 and IDI-6273. Co-crystallisation experiments led to a new crystal form in each case. Here we describe the crystal structures, the binding modes of the inhibitors and the great flexibility of the binding site, which is able to adjust to accommodate different inhibitor series. The structural role of the resistance mutations is also discussed.

scholarly journals The human erythrocyte anion transport protein, band 3. Characterization of exofacial alkaline titratable groups involved in anion binding/translocation.

1992 ◽  
Vol 100 (2) ◽  
pp. 301-339 ◽  
Author(s):  
P J Bjerrum
Keyword(s):  
Ionic Strength ◽  
Binding Site ◽  
Transport System ◽  
Human Erythrocyte ◽  
Binding Constant ◽  
Anion Transport ◽  
High Ionic Strength ◽  
Anion Binding ◽  
Asymmetry Factor ◽  
Sensitive Group

Chloride self-exchange across the human erythrocyte membrane at alkaline extracellular pH (pHO) and constant neutral intracellular pH (pH(i)) can be described by an exofacial deprotonatable reciprocating anion binding site model. The conversion of the transport system from the neutral to the alkaline state is related to deprotonation of a positively charged ionic strength- and substrate-sensitive group. In the absence of substrate ions ([ClO] = 0) the group has a pK of approximately 9.4 at constant high ionic strength (equivalent to approximately 150 mM KCl) and a pK of approximately 8.7 at approximately zero ionic strength. The alkaline ping-pong system (examined at constant high ionic strength) demonstrates outward recruitment of the binding sites with an asymmetry factor of approximately 0.2, as compared with the inward recruitment of the transport system at neutral pHO with an asymmetry factor of approximately 10. The intrinsic half-saturation constant for chloride binding, with [Cli] = [Clo], increased from approximately 30 mM at neutral to approximately 110 mM at alkaline pHO. The maximal transport rate was a factor of approximately 1.7 higher at alkaline pHO. This increase explains the stimulation of anion transport, the "modifier hump," observed at alkaline pHO. The translocation of anions at alkaline pHO was inhibited by deprotonation of another substrate-sensitive group with an intrinsic pK of approximately 11.3. This group together with the group with a pK of approximately 9.4 appear to form the essential part of the exofacial anion binding site. The effect of extracellular iodide inhibition on chloride transport as a function of pHO could, moreover, be simulated if three extracellular iodide binding constants were included in the model: namely, a competitive intrinsic iodide binding constant of approximately 1 mM in the neutral state, a self-inhibitor binding constant of approximately 120 mM in the neutral state, and a competitive intrinsic binding constant of approximately 38 mM in the alkaline state.

scholarly journals Mouse Bestrophin-2 Is a Bona fide Cl− Channel

2004 ◽  
Vol 123 (4) ◽  
pp. 327-340 ◽  
Author(s):  
Zhiqiang Qu ◽  
Rodolphe Fischmeister ◽  
Criss Hartzell
Keyword(s):  
Binding Site ◽  
Cell Lines ◽  
Electrostatic Interactions ◽  
Anion Binding ◽  
Wild Type ◽  
Cl Channel ◽  
Mammalian Cell Lines ◽  
Conduction Pathway ◽  
Bona Fide ◽  
Cl Conductance

Bestrophins have recently been proposed to comprise a new family of Cl− channels. Our goal was to test whether mouse bestrophin-2 (mBest2) is a bona fide Cl− channel. We expressed mBest2 in three different mammalian cell lines. mBest2 was trafficked to the plasma membrane as shown by biotinylation and immunoprecipitation, and induced a Ca2+-activated Cl− current in all three cell lines (EC50 for Ca2+ = 230 nM). The permeability sequence was SCN−: I−: Br−: Cl−: F− (8.2: 1.9: 1.4: 1: 0.5). Although SCN− was highly permeant, its conductance was ∼10% that of Cl− and SCN− blocked Cl− conductance (IC50 = 12 mM). Therefore, SCN− entered the pore more easily than Cl−, but bound more tightly than Cl−. Mutations in S79 altered the relative permeability and conductance for SCN− as expected if S79 contributed to an anion binding site in the channel. PSCN/PCl = 8.2 ± 1.3 for wild-type and 3.9 ± 0.4 for S79C. GSCN/GCl = 0.14 ± 0.03 for wild-type and 0.94 ± 0.04 for S79C. In the S79 mutants, SCN− did not block Cl− conductance. This suggested that the S79C mutation altered the affinity of an anion binding site for SCN−. Additional evidence that S79 was located in the conduction pathway was provided by the finding that modification of the sulfhydryl group in S79C with MTSET+ or MTSES− increased conductance significantly. Because the effect of positively and negatively charged MTS reagents was similar, electrostatic interactions between the permeant anion and the channel at this residue were probably not critical in anion selectivity. These data provide strong evidence that mBest2 forms part of the novel Cl− conduction pathway in mBest2-transfected cells and that S79 plays an important role in anion binding in the pore of the channel.

scholarly journals Highly Efficient, Tripodal Ion-Pair Receptors for Switching Selectivity between Acetates and Sulfates Using Solid–Liquid and Liquid–Liquid Extractions

2020 ◽  
Vol 21 (24) ◽  
pp. 9465
Author(s):  
Marta Zaleskaya ◽  
Łukasz Dobrzycki ◽  
Jan Romański
Keyword(s):  
Binding Sites ◽  
Liquid Extraction ◽  
Ion Pair ◽  
Anion Binding ◽  
Binding Modes ◽  
Anion Receptor ◽  
X Ray ◽  
Liquid Liquid Extraction ◽  
Solid Liquid Extraction ◽  
Solid Liquid

A tripodal, squaramide-based ion-pair receptor 1 was synthesized in a modular fashion, and 1H NMR and UV-vis studies revealed its ability to interact more efficiently with anions with the assistance of cations. The reference tripodal anion receptor 2, lacking a crown ether unit, was found to lose the enhancement in anion binding induced by presence of cations. Besides the ability to bind anions in enhanced manner by the “single armed” ion-pair receptor 3, the lack of multiple and prearranged binding sites resulted in its much lower affinity towards anions than in the case of tripodal receptors. Unlike with receptors 2 or 3, the high affinity of 1 towards salts opens up the possibility of extracting extremely hydrophilic sulfate anions from aqueous to organic phase. The disparity in receptor 1 binding modes towards monovalent anions and divalent sulfates assures its selectivity towards sulfates over other lipophilic salts upon liquid–liquid extraction (LLE) and enables the Hofmeister bias to be overcome. By changing the extraction conditions from LLE to SLE (solid–liquid extraction), a switch of selectivity from sulfates to acetates was achieved. X-ray measurements support the ability of anion binding by cooperation of the arms of receptor 1 together with simultaneous binding of cations.

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