title: The solution structure of omega-Aga-IVB, a P-type calcium channel antagonist from venom of the funnel web spider, Agelenopsis aperta.
abstract: The 48 amino acid peptides omega-Aga-IVA and omega-Aga-IVB are the first agents known to specifically block P-type calcium channels in mammalian brain, thus complementing the existing suite of pharmacological tools used for characterizing calcium channels. These peptides provide a new set of probes for studies aimed at elucidating the structural basis underlying the subtype specificity of calcium channel antagonists. We used 288 NMR-derived constraints in a protocol combining distance geometry and molecular dynamics employing the program DGII, followed by energy minimization with Discover to derive the three-dimensional structure of omega-Aga-IVB. The toxin consists of a well-defined core region, comprising seven solvent-shielded residues and a well-defined triple-stranded beta-sheet. Four loop regions have average backbone rms deviations between 0.38 and 1.31 A, two of which are well-defined type-II beta-turns. Other structural features include disordered C- and N-termini and several conserved basic amino acids that are clustered on one face of the molecule. The reported structure suggests a possible surface for interaction with the channel. This surface contains amino acids that are identical to those of another known P-type calcium channel antagonist, omega-Aga-IVA, and is rich in basic residues that may have a role in binding to the anionic sites in the extracellular regions of the calcium channel.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, MI 48105.
authors.forename: M D
authors.initials: MD
authors.lastname: Reily
authors.forename: V
authors.initials: V
authors.lastname: Thanabal
authors.forename: M E
authors.initials: ME
authors.lastname: Adams
mesh_terms: D060848:Agatoxins; D000595:Amino Acid Sequence; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D004220:Disulfides / Q000737:chemistry; D004563:Electrochemistry; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D012996:Solutions; D013111:Spider Venoms / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D013112:Spiders
chemical_list: D060848:Agatoxins; D002121:Calcium Channel Blockers; D004220:Disulfides; D012996:Solutions; D013111:Spider Venoms; C083855:omega-agatoxin-Aa4b