1ie6
SOLUTION STRUCTURE OF IMPERATOXIN A
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OverviewOverview
Both imperatoxin A (IpTx(a)), a 33-residue peptide toxin from scorpion, venom, and peptide A, derived from the II-III loop of dihydropyridine, receptor (DHPR), interact specifically with the skeletal ryanodine, receptor (RyR1), which is a Ca(2+)-release channel in the sarcoplasmic, reticulum, but with considerably different affinities. IpTx(a) activates, RyR1 with nanomolar affinity, whereas peptide A activates RyR1 at, micromolar concentrations. To investigate the molecular basis for, high-affinity activation of RyR1 by IpTx(a), we have determined the NMR, solution structure of IpTx(a), and identified its functional surface by, using alanine-scanning analogues. A detailed comparison of the functional, surface profiles for two peptide activators revealed that IpTx(a) exhibits, a large functional surface area (approx. 1900 A(2), where 1 A=0.1 nm), based on a short double-stranded antiparallel beta-sheet structure, while, peptide A bears a much smaller functional surface area (approx. 800 A(2)), with the five consecutive basic residues (Arg(681), Lys(682), Arg(683), Arg(684) and Lys(685)) being clustered at the C-terminal end of the, alpha-helix. The functional surface of IpTx(a) is composed of six, essential residues (Leu(7), Lys(22), Arg(23), Arg(24), Arg(31) and, Arg(33)) and several other important residues (His(6), Lys(8), Arg(9), Lys(11), Lys(19), Lys(20), Gly(25), Thr(26), Asn(27) and Lys(30)), indicating that amino acid residues involved in RyR1 activation make up, over the half of the toxin molecule with the exception of cysteine, residues. Taken together, these results suggest that the site where, peptide A binds to RyR1 belongs to a subset of macrosites capable of being, occupied by IpTx(a), resulting in differing the affinity and the mode of, activation.
About this StructureAbout this Structure
1IE6 is a Single protein structure of sequence from [1]. Full crystallographic information is available from OCA.
ReferenceReference
Molecular basis of the high-affinity activation of type 1 ryanodine receptors by imperatoxin A., Lee CW, Lee EH, Takeuchi K, Takahashi H, Shimada I, Sato K, Shin SY, Kim DH, Kim JI, Biochem J. 2004 Jan 15;377(Pt 2):385-94. PMID:14535845
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