Acetylcholine Binding by a Synthetic Receptor: Implications for Biological Recognition

Dougherty, Dennis A.; Stauffer, David A.

doi:10.1126/science.2274786

Cited by 629 publications

(361 citation statements)

References 32 publications

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“…The active site contains a catalytic triad and an oxyanion hole, similar to those found in other serine hydrolases (Steitz & Shulman, 1982), an acyl pocket which recognizes the acetyl group (Harel et al, 1992) and a so-called`anionic site', which recognizes the quaternary group of ACh. Surprisingly, the principal component of this anionic site is not a cluster of negative charges, as previously postulated (Nolte et al, 1980), but rather the indole moiety of Trp84, which makes a %±cation interaction (Dougherty & Stauffer, 1990;Felder et al, 2001) with the quaternary group of ACh (Sussman et al, 1991). A second aromatic residue, Phe330, is also involved in recognition of quaternary ligands and, perhaps, also of ACh (Harel et al, 1993).…”

Section: Introductionmentioning

confidence: 94%

“…More recently, the importance of the interaction of aromatic residues with cationic species via cation±% interactions has also been realised (Dougherty & Stauffer, 1990;Felder et al, 2001;Gallivan & Dougherty, 1999;Sussman et al, 1991;Verdonk et al, 1993). Although both types of interactions are obviously important for ligand±protein interactions, it has not proved easy to quantify their relative contributions.…”

Section: Introductionmentioning

confidence: 99%

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Structure of a complex of the potent and specific inhibitor BW284C51 withTorpedo californicaacetylcholinesterase

Felder

Harel

Silman

et al. 2002

Acta Crystallogr D Biol Cryst

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The X-ray crystal structure of Torpedo californica acetylcholinesterase (TcAChE) complexed with BW284C51 {CO[ÐCH 2 CH 2 ÐpC 6 H 4 ÐN(CH 3 ) 2 (CH 2 ÐCH CH 2 )] 2 } is described and compared with the complexes of two other active-site gorge-spanning inhibitors, decamethonium and E2020. The inhibitor was soaked into TcAChE crystals in the trigonal space group P3 1 21, yielding a complex which diffracted to 2.85 A Ê resolution. The structure was re®ned to an R factor of 19.0% and an R free of 23.4%; the ®nal model contains the protein, inhibitor, 132 water molecules and three carbohydrate moieties. BW284C51 binds similarly to decamethonium and E2020, with its two phenyl and quaternary amino end-groups complexed to Trp84 in the catalytic site and to Trp279 in the peripheral binding site, and its central carbonyl group hydrogen bonded very weakly to Tyr121. Possible reasons for decamethonium's weaker binding are considered. The relative strength of binding of bisquaternary inhibitors to acetylcholinesterase and the effect of several mutations of the enzyme are discussed in the context of the respective X-ray structures of their complexes with the enzyme.

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Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Structure of a complex of the potent and specific inhibitor BW284C51 withTorpedo californicaacetylcholinesterase

Felder

Harel

Silman

et al. 2002

Acta Crystallogr D Biol Cryst

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“…The uptake of TPB results in a more favourable environment for positively charged ions, such as TPP, to cross. The presence of TPB within the lipid bilayer may compete with TPP for sites present in the K+ channel, but since TPB cannot occupy the negatively charged environment of the ion channel itself, it does not impede ion move-ment (see Sunner et al, 1981;Stauffer & Dougherty, 1988;Dougherty & Stauffer, 1990 for additional details). It is an intriguing possibility that TPB may prove to be an 'unblocker' of all K+ channels (and possibly other ion channels) where the blockade results from channel plugging as may be the case with TEA and TPP.…”

Section: The Antagonism Displayed By the Quaternary Ionsmentioning

confidence: 99%

Antagonism by lipophilic quaternary ions of the K⁺ channel opener, levcromakalim, in vascular smooth muscle

McPherson

Piekarska

1994

British J Pharmacology

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1 The aim of this study was to characterize the interaction between the K+ channel opener levcromakalim (LKM) and several quaternary ions, in vascular smooth muscle, in vitro. Segments of isolated, thoracic aorta of the rat were suspended in organ baths filled with Krebs solution at 37C. Cumulative concentration-response curves to LKM were obtained in the absence and in the presence of increasing concentrations of quaternary ions using a number of agents to pre-constrict the vessel. The ions tested were tetraphenylphosphonium (chloride TPP-C1 and bromide TPP-Br salts), tetrapentylammonium (TPeA), tetraethylammonium (TEA), tetraphenylarsonium (TPAs) and tetraphenylboron (TPB). 2 For the compounds which antagonized the vasorelaxation responses of LKM, 'apparent pKB' values were estimated on the basis of a single concentration of antagonist. These were then used to obtain the following order of potency: TPP-Br (7.22 ± 0.25) = TPAs (7.12 ± 0.04) = TPP-Cl (7.11 ± 0.15) > TPeA (6.23 ± 0.20). TEA and TPB were both found to be inactive at the maximum concentrations used. 3 The interaction between the cationic TPP and anionic TPB was also investigated. The shift in the LKM concentration-response curve constructed in the presence of both of these compounds was compared to that when each agent was present separately. We found that TPB, at concentrations greater than 1 gLM, reversed the blockade of the LKM-mediated relaxation induced by TPP (3 IsM). 4 Similar experiments were undertaken combining TPB with either alinidine or glibenclamide (both functional antagonists of K+ channel openers). It was found that TPB (10 gM) partially reversed the antagonism induced by alinidine (30 and 100 gM) but had no effect on the action of glibenclamide (3 gM). 5These studies show that lipophilic cations such as TPP and TPAs are potent antagonists of levcromakalim-mediated vasorelaxation responses in the rat thoracic aorta. The mechanism by which these compounds cause their antagonism is not known. However, given the lipophilicity of these compounds, it is possible they may act at a number of sites including the KATP channel itself or possibly via some other intracellular mechanism.

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“…Motif II is unusually rich in aromatic amino acids (Tyr, Trp, and Phe), which are located around a central invariant aspartate residue (27). Aromatic rings are considered to be involved in binding SAM through cation-quadrapole interactions with the positively charged sulfonium moiety of SAM (13,31). The importance of tyrosine in motif II of rat guanidinoacetate methyltransferase (RGAMT) has already been demonstrated (22).…”

mentioning

confidence: 99%

Escherichia coli TehB Requires S -Adenosylmethionine as a Cofactor To Mediate Tellurite Resistance

et al. 2000

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The Escherichia coli chromosomal determinant for tellurite resistance consists of two genes (tehA and tehB) which, when expressed on a multicopy plasmid, confer resistance to K 2 TeO 3 at 128 g/ml, compared to the MIC of 2 g/ml for the wild type. TehB is a cytoplasmic protein which possesses three conserved motifs (I, II, and III) found in S-adenosyl-L-methionine (SAM)-dependent non-nucleic acid methyltransferases. Replacement of the conserved aspartate residue in motif I by asparagine or alanine, or of the conserved phenylalanine in motif II by tyrosine or alanine, decreased resistance to background levels. Our results are consistent with motifs I and II in TehB being involved in SAM binding. Additionally, conformational changes in TehB are observed upon binding of both tellurite and SAM. The hydrodynamic radius of TehB measured by dynamic light scattering showed a ϳ20% decrease upon binding of both tellurite and SAM. These data suggest that TehB utilizes a methyltransferase activity in the detoxification of tellurite.Tellurite (TeO 3 2Ϫ ) resistance, which is found in many microorganisms (37), is carried on plasmids of IncHI, IncHII, and IncP incompatibility groups (3, 36, 39) and/or on chromosomes (9, 10, 29, 33). Tellurite resistance (Te r ) determinants are very diverse, and at least five different determinants have been identified (37). Te r determinants are unrelated, and probably different resistance mechanisms are involved. Except for that encoded by the Pseudomonas syringae tpm gene, Te r mechanisms are not clearly understood. tpm encodes a methyltransferase that catalyzes S-adenosyl-L-methionine (SAM) methylation of 6-mercaptopurine, a substrate for human thiopurine methyltransferase. It was assumed that tellurite is also a substrate for this enzyme (11).The Te r determinant tehAB, an operon located at 32.3 min on the Escherichia coli K-12 chromosome (38), encodes proteins of 330 (TehA) and 197 (TehB) amino acids. TehA is a membrane protein with 10 transmembrane segments, whereas TehB is a soluble protein. The closest homologues of these two genes are found in Haemophilus influenzae (15).A sequence search performed with the BLAST program (National Center for Biotechnology Information), followed by alignment analysis with the Genetics Computer Group software package (University of Wisconsin) (12), demonstrated that TehB displays some amino acid sequence similarity to many SAM-dependent non-nucleic acid methyltransferases. These proteins have three shared motifs, and the TehB proteins show homologies within all regions with comparable sequence interval distances (Fig.

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Acetylcholine Binding by a Synthetic Receptor: Implications for Biological Recognition

Cited by 629 publications

References 32 publications

Structure of a complex of the potent and specific inhibitor BW284C51 withTorpedo californicaacetylcholinesterase

Structure of a complex of the potent and specific inhibitor BW284C51 withTorpedo californicaacetylcholinesterase

Antagonism by lipophilic quaternary ions of the K⁺ channel opener, levcromakalim, in vascular smooth muscle

Escherichia coli TehB Requires S -Adenosylmethionine as a Cofactor To Mediate Tellurite Resistance

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Acetylcholine Binding by a Synthetic Receptor: Implications for Biological Recognition

Cited by 629 publications

References 32 publications

Structure of a complex of the potent and specific inhibitor BW284C51 withTorpedo californicaacetylcholinesterase

Structure of a complex of the potent and specific inhibitor BW284C51 withTorpedo californicaacetylcholinesterase

Antagonism by lipophilic quaternary ions of the K+ channel opener, levcromakalim, in vascular smooth muscle

Escherichia coli TehB Requires S -Adenosylmethionine as a Cofactor To Mediate Tellurite Resistance

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Antagonism by lipophilic quaternary ions of the K⁺ channel opener, levcromakalim, in vascular smooth muscle