Crystal Structure of ctx a3 and Hexasaccharide Heparin Complex from Naja Atra

Дата канвертавання24.04.2016
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Crystal Structure of CTX A3 and Hexasaccharide Heparin Complex from Naja Atra
Hong-Hsiang Guan (管泓翔)1, 2, Shao-Chen Lee (李紹禎)2,

Wen-Guey Wu (吳文桂)2, and Chung-Jung Chen (陳俊榮)1

1Biology Group, National Synchrotron Radiation Research Center, Hsinchu, Taiwan

2Department of Life Sciences and Structural Biology Program, Tsing Hua University, Hsinchu, Taiwan
Cardiotoxin (CTX) is a major component of cobra toxin. Cobra cardiotoxins (CTXs) are basic proteins, composed of 60-62 amino acids, in which β-sheets form three finger-loop structures. When cobra bites animals or human, CTX can induce tissue inflammation. However, the CTX major target on cell membrane is still unclear now. Our previous studies have proved that heparan sulfate is the most potential target of CTX on cell membrane. We have determined the crystal structure of CTX A3 and hexasaccharide complex at 3.4 Å resolution using synchrotron radiation X-ray. Through the complex structure, we found that citrate anion plays an important role in prompting CTX A3 to form dimmer by interacting with Lys31 and Lys23. The finding is important because anionic citrate is a major component (~50mM) of venom, but the specific role of citrate is still poorly understood. Besides, Hexasaccharide heparin bind to CTX A3 by interacting with positively charged residue Lys12, Lys18 and Lys35. The binding site of hexasaccharide heparin from X-ray is similar to that of the disaccharide from NMR study. It is also worthy to discuss that one of CTX A3 dimmer is heparin bound form and the other is heparin non-bound form. This study suggests a novel role for venom citrate activity and identify specific sulfation pattern of heparan sulfate in binding to CTX A3.

[1] Wu, W. (1998) Trends. Cardiovas. Med. 8, 270-278

[2] Vyas, A.A., Pan, J., Patel, H.V., Vyas, K.A., Chiang, Sheu, Y. Hwang, J., and Wu, W. (1997) J. Biol. Chem. 272, 9661-9670.

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