1ahl
From Proteopedia
ANTHOPLEURIN-A,NMR, 20 STRUCTURES
Structural highlights
FunctionNA1A_ANTXA Binds specifically to voltage-gated sodium channels (Nav) (site 3), thereby delaying their inactivation. This toxin retains the greatest capacity to discriminate between the cardiac (Nav1.5/SCN5A) and neuronal sodium channels (2.5 nM versus 120 nM, when electrophysiologically tested and 14 nM versus 400 nM, when tested by ion flux), whereas its paralog Anthopleurin-B has the highest affinity of all anemone toxins for the mammalian sodium channel (PubMed:13806, PubMed:17092528, PubMed:7612595). Its ability to differentiate between cardiac and skeletal channels appears to be associated with domain 4 of the channel (PubMed:9306007). This toxin does not slow or inhibit closed-state inactivation of cardiac sodium channels, but selectively modifies inactivation from the open-state (PubMed:8576699). It does not display phospholipid-binding activities, suggesting that the domain IV S3-S4 linker is located at the extracellular surface and not buried in the phospholipid bilayer (By similarity).[UniProtKB:P01531][1] [2] [3] [4] [5] 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 PubMedThe three-dimensional structure in aqueous solution of the 49-residue polypeptide anthopleurin-A (AP-A), from the sea anemone Anthopleura xanthogrammica, has been determined from 1H NMR data. A restraint set consisting of 411 interproton distance restraints inferred from NOEs and 19 backbone and 13 side chain dihedral angle restraints from spin-spin coupling constants, as well as 15 lower bound restraints based on the absence of NOEs in the spectra, was used as input for distance geometry calculations in DIANA and simulated annealing and restrained energy minimization in X-PLOR. Stereospecific assignments for 12 beta-methylene pairs were also included. The final set of 20 structures had mean pairwise rms differences over the whole molecule of 2.04 A for the backbone heavy atoms (N, C alpha, and C) and 2.59 A for all heavy atoms. For the well-defined region encompassing residues 2-7 and 17-49, the corresponding values were 0.82 and 1.27 A, respectively. AP-A adopts a compact structure consisting of four short strands of antiparallel beta-sheet (residues 2-4, 20-23, 34-37, and 45-48) connected by three loops. The first loop commences with a type I beta-turn which includes two important Asp residues; this loop is the least well-defined region of the protein, although a beta-turn involving residues 13-16 is observed in nearly half the structures. The loop linking the second and third strands is constrained by the 29-47 disulfide bond and contains two well-defined beta-turns, while the third loop contains the Gly40-Pro41 sequence, which has been identified previously as the site of cis-trans isomerism. The carboxylate group of Asp7 is close to the epsilon-ammonium group of Lys37, suggesting that they may form a salt bridge. A pH titration monitored by 2D NMR supports this by showing that Asp7 has a low pKa. It is proposed that this region of the molecule and the nearby residues Asp9 and His39 form part of the molecular surface which interacts with the mammalian cardiac sodium channel. Three-dimensional structure in solution of the polypeptide cardiac stimulant anthopleurin-A.,Pallaghy PK, Scanlon MJ, Monks SA, Norton RS Biochemistry. 1995 Mar 21;34(11):3782-94. PMID:7893675[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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