2uz6
From Proteopedia
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'''ACHBP-TARGETED A-CONOTOXIN CORRELATES DISTINCT BINDING ORIENTATIONS WITH NACHR SUBTYPE SELECTIVITY.''' | '''ACHBP-TARGETED A-CONOTOXIN CORRELATES DISTINCT BINDING ORIENTATIONS WITH NACHR SUBTYPE SELECTIVITY.''' | ||
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[[Category: Smit, A B.]] | [[Category: Smit, A B.]] | ||
[[Category: Ulens, C.]] | [[Category: Ulens, C.]] | ||
| - | [[Category: | + | [[Category: Receptor]] |
| - | [[Category: | + | [[Category: Soluble acetylcholine receptor]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 17:51:21 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 14:51, 4 May 2008
ACHBP-TARGETED A-CONOTOXIN CORRELATES DISTINCT BINDING ORIENTATIONS WITH NACHR SUBTYPE SELECTIVITY.
Overview
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.
About this Structure
2UZ6 is a Protein complex structure of sequences from Aplysia californica. Full crystallographic information is available from OCA.
Reference
AChBP-targeted alpha-conotoxin correlates distinct binding orientations with nAChR subtype selectivity., Dutertre S, Ulens C, Buttner R, Fish A, van Elk R, Kendel Y, Hopping G, Alewood PF, Schroeder C, Nicke A, Smit AB, Sixma TK, Lewis RJ, EMBO J. 2007 Aug 22;26(16):3858-67. Epub 2007 Jul 26. PMID:17660751 Page seeded by OCA on Sun May 4 17:51:21 2008
