title: Design and synthesis of peptides that bind alpha-bungarotoxin with high affinity and mimic the three-dimensional structure of the binding-site of acetylcholine receptor.
abstract: Alpha-bungarotoxin (alpha-BTX) is a highly toxic snake neurotoxin that binds to acetylcholine receptor (AChR) at the neuromuscular junction, and is a potent inhibitor of this receptor. In the following we review multi-phase research of the design, synthesis and structure analysis of peptides that bind alpha-BTX and inhibit its binding to AChR. Structure-based design concomitant with biological information of the alpha-BTX/AChR system yielded 13-mer peptides that bind to alpha-BTX with high affinity and are potent inhibitors of alpha-BTX binding to AChR (IC(50) of 2 nM). X-Ray and NMR spectroscopy reveal that the high-affinity peptides fold into an anti-parallel beta-hairpin structure when bound to alpha-BTX. The structures of the bound peptides and the homologous loop of acetylcholine binding protein, a soluble analog of AChR, are remarkably similar. Their superposition indicates that the toxin wraps around the binding-site loop, and in addition, binds tightly at the interface of two of the receptor subunits and blocks access of acetylcholine to its binding site. The procedure described in this article may serve as a paradigm for obtaining high-affinity peptides in biochemical systems that contain a ligand and a receptor molecule.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. ephraim.katzir@weizmann.ac.il
authors.forename: Ephraim
authors.initials: E
authors.lastname: Katchalski-Katzir
authors.forename: Roni
authors.initials: R
authors.lastname: Kasher
authors.forename: Moshe
authors.initials: M
authors.lastname: Balass
authors.forename: Tali
authors.initials: T
authors.lastname: Scherf
authors.forename: Michal
authors.initials: M
authors.lastname: Harel
authors.forename: Mati
authors.initials: M
authors.lastname: Fridkin
authors.forename: Joel L
authors.initials: JL
authors.lastname: Sussman
authors.forename: Sara
authors.initials: S
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D002038:Bungarotoxins / Q000737:chemistry* / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018716:Molecular Mimicry; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis*; D011485:Protein Binding; D011487:Protein Conformation; D011950:Receptors, Cholinergic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014101:Torpedo
chemical_list: D002038:Bungarotoxins; D019151:Peptide Library; D010455:Peptides; D011950:Receptors, Cholinergic