PDBsum entry 5afm

Transport protein

PDB id: 5afm

Contents

Protein chains

205 a.a.

Ligands

NAG ×10

L0B ×5

GOL ×4

9Z0 ×5

Waters ×328

PDB id:

5afm

Name:

Transport protein

Title:

Alpha7-achbp in complex with lobeline and fragment 4

Structure:

Acetylcholine-binding protein, neuronal acetylcholine receptor subunit alpha-7. Chain: a, c, d, e. Synonym: alpha7-achbp, ach-binding protein, achbp. Engineered: yes. Acetylcholine-binding protein, neuronal acetylcholine receptor subunit alpha-7. Chain: b. Synonym: alpha7-achbp, ach-binding protein, achbp.

Source:

Homo sapiens, lymnaea stagnalis. Human, great pond snail. Organism_taxid: 9606, 6523. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21. Human, great pond snail, human. Expression_system_cell_line: sf21

Resolution:

2.85Å R-factor: 0.164 R-free: 0.217

Authors:

R.Spurny,S.Debaveye,A.Farinha,K.Veys,T.Gossas,J.Atack,D.Bertrand, J.Kemp,A.Vos,U.H.Danielson,G.Tresadern,C.Ulens

Key ref:

R.Spurny et al. (2015). Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor. Proc Natl Acad Sci U S A, 112, E2543. PubMed id: 25918415 DOI: 10.1073/pnas.1418289112

Date:

22-Jan-15 Release date: 06-May-15

Protein chains

P36544  (ACHA7_HUMAN) -  Neuronal acetylcholine receptor subunit alpha-7 from Homo sapiens

Seq: 502 a.a.

Struc: 205 a.a.*

Protein chains

P58154  (ACHP_LYMST) -  Acetylcholine-binding protein from Lymnaea stagnalis

Seq: 229 a.a.

Struc: 205 a.a.*

* PDB and UniProt seqs differ at 152 residue positions (black crosses)

DOI no: 10.1073/pnas.1418289112

Proc Natl Acad Sci U S A 112:E2543 (2015)

PubMed id: 25918415

Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor.

R.Spurny, S.Debaveye, A.Farinha, K.Veys, A.M.Vos, T.Gossas, J.Atack, S.Bertrand, D.Bertrand, U.H.Danielson, G.Tresadern, C.Ulens.

ABSTRACT

The α7 nicotinic acetylcholine receptor (nAChR) belongs to the family of pentameric ligand-gated ion channels and is involved in fast synaptic signaling. In this study, we take advantage of a recently identified chimera of the extracellular domain of the native α7 nicotinic acetylcholine receptor and acetylcholine binding protein, termed α7-AChBP. This chimeric receptor was used to conduct an innovative fragment-library screening in combination with X-ray crystallography to identify allosteric binding sites. One allosteric site is surface-exposed and is located near the N-terminal α-helix of the extracellular domain. Ligand binding at this site causes a conformational change of the α-helix as the fragment wedges between the α-helix and a loop homologous to the main immunogenic region of the muscle α1 subunit. A second site is located in the vestibule of the receptor, in a preexisting intrasubunit pocket opposite the agonist binding site and corresponds to a previously identified site involved in positive allosteric modulation of the bacterial homolog ELIC. A third site is located at a pocket right below the agonist binding site. Using electrophysiological recordings on the human α7 nAChR we demonstrate that the identified fragments, which bind at these sites, can modulate receptor activation. This work presents a structural framework for different allosteric binding sites in the α7 nAChR and paves the way for future development of novel allosteric modulators with therapeutic potential.