ABCC7 p.Phe494Gly
| Predicted by SNAP2: | A: N (78%), C: N (72%), D: D (66%), E: N (53%), G: N (53%), H: N (66%), I: N (87%), K: N (57%), L: N (82%), M: N (72%), N: N (72%), P: D (66%), Q: N (61%), R: N (57%), S: N (66%), T: N (78%), V: N (93%), W: N (53%), Y: N (87%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Molecular modeling of the heterodimer of human CFT... J Mol Graph Model. 2009 Apr;27(7):822-8. Epub 2008 Dec 24. Huang SY, Bolser D, Liu HY, Hwang TC, Zou X
Molecular modeling of the heterodimer of human CFTR's nucleotide-binding domains using a protein-protein docking approach.
J Mol Graph Model. 2009 Apr;27(7):822-8. Epub 2008 Dec 24., [PMID:19167254]
Abstract [show]
We have presented a new protein-protein docking approach to model heterodimeric structures based on the conformations of the monomeric units. The conventional modeling method relies on superimposing two monomeric structures onto the crystal structure of a homologous protein dimer. The resulting structure may exhibit severe backbone clashes at the dimeric interface depending on the backbone dissimilarity between the target and template proteins. Our method overcomes the backbone clashing problem and requires no a priori knowledge of the dimeric structure of a homologous protein. Here we used human Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a chloride channel whose dysfunction causes cystic fibrosis, for illustration. The two intracellular nucleotide-binding domains (NBDs) of CFTR control the opening and closing of the channel. Yet, the structure of the CFTR's NBD1-NBD2 complex has not been experimentally determined. Thus, correct modeling of this heterodimeric structure is valuable for understanding CFTR functions and would have potential applications for drug design for cystic fibrosis treatment. Based on the crystal structure of human CFTR's NBD1, we constructed a model of the NBD1-NBD2 complex. The constructed model is consistent with the dimeric mode observed in the crystal structures of other ABC transporters. To verify our structural model, an ATP substrate was docked into the nucleotide-binding site. The predicted binding mode shows consistency with related crystallographic findings and CFTR functional studies. Finally, genistein, an agent that enhances CFTR activity, though the mechanism for such enhancement is unclear, was docked to the model. Our predictions agreed with genistein's bell-shaped dose-response relationship. Potential mutagenesis experiments were proposed for understanding the potentiation mechanism of genistein and for providing insightful information for drug design targeting at CFTR. The method used in this study can be applied to modeling studies of other dimeric protein structures.
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No. Sentence Comment
221 Our preliminary study with F494G-CFTR using whole-cell electrophysiological recording showed that indeed the apparent affinity of genistein was lowered to 25.3 mM, compared to 4.4 mM for wild-type CFTR (M. Li and T.-C. Hwang, unpublished data).
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ABCC7 p.Phe494Gly 19167254:221:27
status: NEW217 Our preliminary study with F494G-CFTR using whole-cell electrophysiological recording showed that indeed the apparent affinity of genistein was lowered to 25.3 mM, compared to 4.4 mM for wild-type CFTR (M. Li and T.-C. Hwang, unpublished data).
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ABCC7 p.Phe494Gly 19167254:217:27
status: NEW