PDBsum entry 2asg

Membrane protein

PDB id: 2asg

Contents

Protein chains

25 a.a.

25 a.a.

Theoretical model

PDB id:

2asg

Name:

Membrane protein

Title:

Binding domain of non-competitive inhibitors in the alpha3beta4 subtype of nicotinic acetylcholine receptor

Structure:

Neuronal acetylcholine receptor protein. Chain: a, c. Fragment: residues 269-291. Other_details: alpha-3 subunit. Neuronal acetylcholine receptor protein. Chain: b, d, e. Fragment: residues 262-284. Other_details: beta-4 subunit

Source:

Homo sapiens. Human. Human

Authors:

K.Jozwiak,S.Ravichandran,J.R.Collins,I.W.Wainer

Key ref:

K.Jozwiak et al. (2004). Interaction of noncompetitive inhibitors with an immobilized alpha3beta4 nicotinic acetylcholine receptor investigated by affinity chromatography, quantitative-structure activity relationship analysis, and molecular docking. J Med Chem, 47, 4008-4021. PubMed id: 15267239 DOI: 10.1021/jm0400707

Date:

23-Aug-05 Release date: 13-Sep-05

Protein chains

P32297  (ACHA3_HUMAN) -  Neuronal acetylcholine receptor subunit alpha-3 from Homo sapiens

Seq: 505 a.a.

Struc: 24 a.a.*

Protein chains

P30926  (ACHB4_HUMAN) -  Neuronal acetylcholine receptor subunit beta-4 from Homo sapiens

Seq: 498 a.a.

Struc: 24 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1021/jm0400707

J Med Chem 47:4008-4021 (2004)

PubMed id: 15267239

Interaction of noncompetitive inhibitors with an immobilized alpha3beta4 nicotinic acetylcholine receptor investigated by affinity chromatography, quantitative-structure activity relationship analysis, and molecular docking.

K.Jozwiak, S.Ravichandran, J.R.Collins, I.W.Wainer.

ABSTRACT

A large number of drug substances act as noncompetitive inhibitors (NCIs) of the nicotinic acetylcholine receptor (nAChR) by blocking the ion flux through the channel. An affinity chromatography technique has been developed for investigating the interactions between NCIs and the alpha3beta4 subtype of neuronal nAChR. The data obtained from the chromatographic study were used to construct QSAR models of the NCI-nAChR binding with both electronic and steric parameters observed as important descriptors. A molecular model of the transmembrane domain of the alpha3beta4 subtype of nAChR was constructed and used to simulate the docking of a series of NCIs. A key aspect of the model was the discovery of the cleft produced by the incorporation of the bulky phenylalanine moiety into the nonpolar section of the lumen by the beta4 subunit. Quantitatively, the results of docking simulations modeled the experimental affinity data better than QSAR results. The computational approach, combined with the modeling of NCI-nAChR interaction by affinity chromatography, can be used to predict possible toxicities and adverse interactions.