1xt3 | pdb_00001xt3
Structure Basis of Venom Citrate-Dependent Heparin Sulfate-Mediated Cell Surface Retention of Cobra Cardiotoxin A3
Structural highlights
Function[3SA3_NAJAT] Basic protein that binds to cell membrane and depolarizes cardiomyocytes. This cytotoxin also possesses lytic activity on many other cells, including red blood cells (PubMed:8182052). Interaction with sulfatides in the cell membrane induces pore formation and cell internalization. Cytotoxicity is due to pore formation, and to another mechanism independent of membrane-damaging activity. When internalized, it targets the mitochondrial membrane and induces mitochondrial swelling and fragmentation. It inhibits protein kinases C. It binds to the integrin alpha-V/beta-3 (ITGAV/ITGB3) with a moderate affinity (PubMed:16407244). It also binds with high affinity to heparin (PubMed:17685633).[1] [2] [3] [4] [5] [6] [7] 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 PubMedAnionic citrate is a major component of venom, but the role of venom citrate in toxicity other than its inhibitory effect on the cation-dependent action of venom toxins is poorly understood. By immobilizing Chinese hamster ovary cells in microcapillary tubes and heparin on sensor chips, we demonstrated that heparan sulfate-mediated cell retention of the major cardiotoxin (CTX) from the Taiwan cobra, CTX A3, near membrane surfaces is citrate-dependent. X-ray determination of a CTX A3-heparin hexasaccharide complex structure at 2.4 A resolution revealed a molecular mechanism for toxin retention in which heparin-induced conformational changes of CTX A3 lead to citrate-mediated dimerization. A citrate ion bound to Lys-23 and Lys-31 near the tip of loop II stabilizes hydrophobic contact of the CTX A3 homodimer at the functionally important loop I and II regions. Additionally, the heparin hexasaccharide interacts with five CTX A3 molecules in the crystal structure, providing another mechanism whereby the toxin establishes a complex network of interactions that result in a strong interaction with cell surfaces presenting heparan sulfate. Our results suggest a novel role for venom citrate in biological activity and reveal a structural model that explains cell retention of cobra CTX A3 through heparan sulfate-CTX interactions. Structural basis of citrate-dependent and heparan sulfate-mediated cell surface retention of cobra cardiotoxin A3.,Lee SC, Guan HH, Wang CH, Huang WN, Tjong SC, Chen CJ, Wu WG J Biol Chem. 2005 Mar 11;280(10):9567-77. Epub 2004 Dec 6. PMID:15590643[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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