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Crystal Structure of Zinc-Bound Natrin From Naja atraCrystal Structure of Zinc-Bound Natrin From Naja atra
Structural highlights
FunctionCRVP1_NAJAT Inhibits calcium-activated potassium channels (KCa1.1/KCNMA1), voltage-gated potassium channel Kv1.3/KCNA3, and the calcium release channel/ryanodine receptor (RyR). Binds specifically to type 1 RyR (RyR1) from skeletal muscle. Inhibit both the binding of ryanodine to RyR1, and RyR1's calcium-channel activity. Inhibits carbachol-induced muscle contraction and weakly blocks muscle contraction evoked by potassium.[1] [2] [3] [4] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCysteine-rich secretory proteins (CRISPs) have been identified as a toxin family in most animal venoms with biological functions mainly associated with the ion channel activity of cysteine-rich domain (CRD). CRISPs also bind to Zn(2+) at their N-terminal pathogenesis-related (PR-1) domain, but their function remains unknown. Interestingly, similar Zn(2+)-binding site exists in all CRISP family, including those identified in a wide range of organisms. Here, we report that the CRISP from Naja atra (natrin) could induce expression of vascular endothelial cell (EC) adhesion molecules, i.e., intercellular adhesion molecule-1, vascular adhesion molecule-1, and E-selectin, to promote monocytic cell adhesion in a heparan sulfate (HS)- and Zn(2+)-dependent manner. Using specific inhibitors and small interfering RNAs, the activation mechanisms are shown to involve both mitogen-activated protein kinases and nuclear factor-kappaB. Biophysical characterization of natrin by using fluorescence, circular-dichroism, and X-ray crystallographic methods further reveals the presence of two Zn(2+)-binding sites for natrin. The strong binding site is located near the putative Ser-His-Glu catalytic triad of the N-terminal domain. The weak binding site remains to be characterized, but it may modulate HS binding by enhancing its interaction with long chain HS. Our results strongly suggest that natrin may serve as an inflammatory modulator that could perturb wound-healing process of the bitten victim by regulating adhesion molecule expression in ECs. Our finding uncovers a new aspect of the biological role of CRISP family in immune response, and is expected to facilitate future development of new therapeutic strategy for the envenomed victims. Cobra CRISP functions as an inflammatory modulator via a novel Zn2+- and heparan sulfate- dependent transcriptional regulation of endothelial cell adhesion molecules.,Wang YL, Kuo JH, Lee SC, Liu JS, Hsieh YC, Shih YT, Chen CJ, Chiu JJ, Wu WG J Biol Chem. 2010 Oct 2. PMID:20889969[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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