Crystal and molecular structure of bicuculline

Gorinsky, C.; Moss, David S.

doi:10.1007/bf01321855

Cited by 15 publications

(6 citation statements)

References 11 publications

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“…The juxtaposition of the two arginine residues in the GABA A R orthosteric site places the side chain of Arg147 to hydrogen bond with Tyr230 from loop C on the principal side to, in effect, provide a steric block preventing the dioxolophthalide from adopting the orientation observed when in complex with GBP. The crystal structure of bicuculline itself has been determined . Superposition of this structure on that of the models derived from the protein complex structures indicates that, in isolation, a different conformation is observed with the two ring systems rotated about 90° relative to each other (Figure S5 C).…”

Section: Resultsmentioning

confidence: 99%

A Structural Rationale for N‐Methylbicuculline Acting as a Promiscuous Competitive Antagonist of Inhibitory Pentameric Ligand‐Gated Ion Channels

et al. 2020

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Bicuculline, a valued chemical tool in neurosciences research, is a competitive antagonist of specific GABAA receptors and affects other pentameric ligand‐gated ion channels including the glycine, nicotinic acetylcholine and 5‐hydroxytryptamine type 3 receptors. We used a fluorescence‐quenching assay and isothermal titration calorimetry to record low‐micromolar dissociation constants for N‐methylbicuculline interacting with acetylcholine‐binding protein and an engineered version called glycine‐binding protein (GBP), which provides a surrogate for the heteromeric interface of the extracellular domain of the glycine receptor (GlyR). The 2.4 Å resolution crystal structure of the GBP:N‐methylbicuculline complex, sequence and structural alignments reveal similarities and differences between GlyR and the GABAA receptor–bicuculline interactions. N‐methylbicuculline displays a similar conformation in different structures, but adopts distinct orientations enforced by interactions and steric blocks with key residues and plasticity in the binding sites. These features explain the promiscuous activity of bicuculline against the principal inhibitory pentameric ligand‐gated ion channels in the CNS.

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Section: Resultsmentioning

confidence: 99%

A Structural Rationale for N‐Methylbicuculline Acting as a Promiscuous Competitive Antagonist of Inhibitory Pentameric Ligand‐Gated Ion Channels

et al. 2020

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“…All molecular structures used in the study for comparison were obtained from published crystallographic data (Steward et al, 1973;Brehm et al, 1972;Gorinsky and Moss, 1973;Lipkowitz et al, 1988Lipkowitz et al, , 1989Gilardi et al, in preparation) with the exception of trans-3-aminocyclopentane carboxylic acid, which was derived quantum mechanically (see below). Hydrogen atoms that were not available from experiment were added such that proper valence angles and bond lengths were maintained.…”

Section: Methodsmentioning

confidence: 99%

On the GABA_A receptor: A molecular modeling approach

Aprison

Lipkowitz

1989

J of Neuroscience Research

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Bicuculline methobromide, a complex alkaloid, antagonizes in some unknown manner the action of GABA, an important inhibitory transmitter in the CNS. To help understand the mechanism of this antagonism we have employed molecular modeling techniques to assess the similarity and difference between this antagonist and GABA plus four direct GABA agonists. Topological and electronic charge congruence between these five molecules was examined in great detail. It was found that each of the five molecules has three clearly defined atoms that serve as attachment points at the GABAA receptor site. It is hypothesized that an additional negatively charged atom on bicuculline serves as an additional point of attachment that blocks the nearby chloride ion channel. The model presented offers an explanation of why muscimol acts as a better agonist than GABA as well as rationalizing why (+)-bicuculline acts as an antagonist but (-)-bicuculline does not.

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“…Nous avons jug6 int6ressant d'entreprendre l'6tude structurale de la picrotoxine, telle qu'elle est utilis6e en th6rapeutique (notamment comme antidote aux barbituriques), afin de v6rifier l'hypoth~se de la structure de la picrotine dont les relations 6troites avec la picrotoxinine ont 6t6 d6montr6es (Porter, 1967). La comparaison de cette structure avec celle d'autres compos6s analogues, comme par exemple, la bicuculline (Gorinsky & Moss, 1973), devrait contribuer ~t une meilleure compr6hension de leurs actions biologiques. (14) 0(3) -232 (4) 7756 (7) 2218 (3) 110 (4) 275 (13) 64 (2) 8 (9) 87 (5) -14 (13) 0(4) 401 (3) 6640 (6) 1157 (2) 79 (3) 162 (9) 46 (2) -4 (7) 23 (4) -31 (9) 0(5) 1613 (4) 12272 (7) 927 (3) 112 (4) 131 (8) 81 (3) -20 (8) -42 (5) 41 (10) 0(6) 752 (3) 9734 (5) 444 (2) 65 (3) 129 (8) 44 (1) 1 (6) -13 (3) 13 (9) C(51) 3058 (5) -933 (8) 5648 (3) 67 (5) 180 (13) 31 (2) -24 (9) 16 (5) 9 (13) C(52) 3117 (5) -2372 (8) 6308 (4) 66 (4) 133 (12) 51 (2) 18 (9) 19 (5) 10 (12) C(53) 2746 (5) -1742 (10) 7069 (3) 81 (5) 220 (14) 41 (2) 53 (10) 22 (5) -51 (15) C(54) 1539 (5) -748 (9) 6928 (3) 67 (4) 206 (14) 34 (2) -9 (9) 12 (5) -50 (13) C(55) 1972...…”

Section: Introductionunclassified