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Structural Difference between Group I and Group II Cobra Cardiotoxins: X-ray, NMR, and CD Analysis of the Effect of cis -Proline Conformation on Three-Fingered Toxins

2005; American Chemical Society; Volume: 44; Issue: 20 Linguagem: Inglês

10.1021/bi050172e

1943-295X

Ting-Shou Chen, Fong-Yu Chung, Siu-Cin Tjong, King-Siang Goh, Weining Huang, Kun‐Yi Chien, Po-Long Wu, Hua-Ching Lin, Chun‐Jung Chen, Wen‐guey Wu,

Marine Toxins and Detection Methods

Natural homologues of cobra cardiotoxins (CTXs) were classified into two structural subclasses of group I and II based on the amino acid sequence and circular dichroism analysis, but the exact differences in their three-dimensional structures and biological significance remain elusive. We show by circular dichroism, NMR spectroscopic, and X-ray crystallographic analyses of a newly purified group I CTX A6 from eastern Taiwan cobra (Naja atra) venoms that its loop I conformation adopts a type VIa turn with a cis peptide bond located between two proline residues of PPxY. A similar "banana-twisted" conformation can be observed in other group I CTXs and also in cyclolinopeptide A and its analogues. By binding to the membrane environment, group I CTX undergoes a conformational change to adopt a more extended hydrophobic domain with β-sheet twisting closer to the one adopted by group II CTX. This result resolves a discrepancy in the CTX structural difference reported previously between solution as well as crystal state and shows that, in addition to the hydrophobicity, the exact loop I conformation also plays an important role in CTX−membrane interaction. Potential protein targets of group I CTXs after cell internalization are also discussed on the basis of the determined loop I conformation.