2UZ6: Achbp-targeted A-conotoxin Correlates Distinct Binding Orientations With Nachr Subtype Selectivity

Citation:
Abstract
Neuronal nAChRs are a diverse family of pentameric ion channels with wide distribution throughout cells of the nervous and immune systems. However, the role of specific subtypes in normal and pathological states remains poorly understood due to the lack of selective probes. Here, we used a binding assay based on acetylcholine-binding protein (AChBP), a homolog of the nicotinic acetylcholine ligand-binding domain, to discover a novel alpha-conotoxin (alpha-TxIA) in the venom of Conus textile. Alpha-TxIA bound with high affinity to AChBPs from different species and selectively targeted the alpha(3)beta(2) nAChR subtype. A co-crystal structure of Ac-AChBP with the enhanced potency analog TxIA(A10L), revealed a 20 degrees backbone tilt compared to other AChBP-conotoxin complexes. This reorientation was coordinated by a key salt bridge formed between Arg5 (TxIA) and Asp195 (Ac-AChBP). Mutagenesis studies, biochemical assays and electrophysiological recordings directly correlated the interactions observed in the co-crystal structure to binding affinity at AChBP and different nAChR subtypes. Together, these results establish a new pharmacophore for the design of novel subtype-selective ligands with therapeutic potential in nAChR-related diseases.
PDB ID: 2UZ6Download
MMDB ID: 104875
PDB Deposition Date: 2007/4/25
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Aplysia californica
Similar Structures:
Biological Unit for 2UZ6: decameric; determined by author and by software (PISA)
Molecular Components in 2UZ6
Label Count Molecule
Proteins (10 molecules)
5
Soluble Acetylcholine Receptor
Molecule annotation
5
Alpha-conotoxin Txia(a10l)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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