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Titolo:
Binding of correolide to the K(v)1.3 potassium channel: Characterization of the binding domain by site-directed mutagenesis
Autore:
Hanner, M; Green, B; Gao, YD; Schmalhofer, WA; Matyskiela, M; Durand, DJ; Felix, JP; Linde, AR; Bordallo, C; Kaczorowski, GJ; Kohler, M; Garcia, ML;
Indirizzi:
Merck Res Labs, Dept Ion Channels, Rahway, NJ 07065 USA Merck Res Labs Rahway NJ USA 07065 ept Ion Channels, Rahway, NJ 07065 USA Merck Res Labs, Dept Mol Syst, Rahway, NJ 07065 USA Merck Res Labs RahwayNJ USA 07065 s, Dept Mol Syst, Rahway, NJ 07065 USA
Titolo Testata:
BIOCHEMISTRY
fascicolo: 39, volume: 40, anno: 2001,
pagine: 11687 - 11697
SICI:
0006-2960(20011002)40:39<11687:BOCTTK>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
T-CELL ACTIVATION; C-TYPE INACTIVATION; GATED K+ CHANNELS; FUNCTIONAL CONSEQUENCES; PROLINE RESIDUES; ION INTERACTIONS; KV1.3; PORE; CHARYBDOTOXIN; AFFINITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
48
Recensione:
Indirizzi per estratti:
Indirizzo: Garcia, ML Merck Res Labs, Dept Ion Channels, POB 2000, Rahway, NJ 07065 USA Merck Res Labs POB 2000 Rahway NJ USA 07065 ahway, NJ 07065 USA
Citazione:
M. Hanner et al., "Binding of correolide to the K(v)1.3 potassium channel: Characterization of the binding domain by site-directed mutagenesis", BIOCHEM, 40(39), 2001, pp. 11687-11697

Abstract

Correolide is a novel immunosuppressant that inhibits the voltage-gated potassium channel K(v)1.3 [Felix et al. (1999) Biochemistry 38, 4922-4930]. [H-3]Dihydrocorreolide (diTC) binds with high affinity to membranes expressing homotetrameric K(v)1.3 channels, and high affinity diTC binding can be conferred to the diTC-insensitive channel, K(v)3.2, after substitution of three nonconserved residues in S-5 and S-6 with the corresponding amino acidspresent in K(v)1.3 [Harmer et al. (1999) J. Biol. Chem. 274, 25237-25244]. Site-directed mutagenesis along S-5 and S-6 of K(v)1.3 was employed to identify those residues that contribute to high affinity binding of diTC. Binding of monoiodotyrosine-HgTX(1)A19Y/Y37F ([I-125]HgTX(1)A19Y/Y37F) in the external vestibule of the channel was used to characterize each mutant for both tetrameric channel formation and levels of channel expression. Substitutions at Leu(346) and Leu(353) in S-5, and Ala(413), Val(417), Ala(421), Pro(423), and Val(424) in S-6, cause the most dramatic effect on diTC bindingto K(v)1.3. Some of the critical residues in S6 appear to be present in a region of the protein that alters its conformation during channel gating. Molecular modeling of the S-5-S-6 region of K(v)1.3 using the X-ray coordinates of the KcsA channel, and other experimental constraints, yield a template that can be used to dock diTC in the channel. DiTC appears to bind in the water-filled cavity below the selectivity filter to a hydrophobic pocket contributed by the side chains of specific residues. High affinity binding is predicted to be determined by the complementary shape between the bowl-shape of the cavity and the shape of the ligand. The conformational change that occurs in this region of the protein during channel gating may explain the state-dependent interaction of diTC with K(v)1.3.

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Documento generato il 28/09/20 alle ore 15:26:38