1ie6
From Proteopedia
SOLUTION STRUCTURE OF IMPERATOXIN A
Structural highlights
Function[IPTXA_PANIM] Affects the activity of ryanodine-sensitive calcium-release channels RyR1, RyR2 and RyR3. At lower concentrations the toxin increases full openings of the RyRs, and at higher concentrations it inhibits full openings and induce openings to subconductance levels and reduces the number of full conductance openings. The different actions may be attributed to the toxins binding at different sites on the RyRs, with binding at a high-affinity site mediating the increase in full openings and the induction of subconductance states evoked upon binding to a lower-affinity site.[1] [2] [3] Publication Abstract from PubMedBoth 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. 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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