Structure-Based Secondary Structure-Independent Approach To Design Protein Ligands: Application to the Design of Kv1.2 Potassium Channel Blockers.
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| Title: | Structure-Based Secondary Structure-Independent Approach To Design Protein Ligands: Application to the Design of Kv1.2 Potassium Channel Blockers. |
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| Authors: | Magis, C.1, Gasparini, D.1, Lecoq, A.1, Le Du, M. H.1, Stura, E.1, Charbonnier, J. B.1, Mourier, G.1, Boulain, J.-C.1, Pardo, L.1, Caruana, A.1, Joly, A.1, Lefranc, M.1, Masella, M.1, Menez, A.1, Cuniasse, P.1 philippe.cuniasse@cea.fr |
| Source: | Journal of the American Chemical Society. 12/20/2006, Vol. 128 Issue 50, p16190-16205. 16p. 1 Diagram, 7 Charts. |
| Subjects: | Protein engineering, Ligand binding (Biochemistry), Radioligand assay, Ligands (Chemistry), Potassium channels, Topology |
| Abstract: | We have developed a structure-based approach to the design of protein ligands. This approach is based on the transfer of a functional binding motif of amino acids, often referred as to the ‘hot spot’, on a host protein able to reproduce the functional topology of these residues. The scaffolds were identified by a systematic in silico search in the Protein Data Bank for proteins possessing a group of residues in a topology similar to that adopted by the functional motif in a reference ligand of known 3D structure. In contrast to previously reported studies, this search is independent of the particular secondary structure supporting the functional motif. To take into account the global properties of the host protein, two additional criteria were taken into account in the selection process: (1) Only those scaffolds sterically compatible with the positioning of the functional motif as observed in a reference complex model were retained. (2) Host proteins displaying electrostatic potentials, in the region of the transferred functional motif, similar to that of the reference ligand were selected. This approach was applied to the development of protein ligands of the Kvl .2 channel using BgK, a small protein isolated from the sea anemone Bunodosoma granulifera, as the reference ligand. Four proteins obtained by this approach were produced for experimental evaluation. The X-ray structure of one of these proteins was determined to check for similarity of the transferred functional motif with the structure it adopts in the reference ligand. Three of these protein ligands bind the Kvl .2 channel with inhibition constants of 0.5, 1.5, and 1.6 μM. Several mutants of these designed protein ligands gave binding results consistent with the presumed binding mode. These results show that protein ligands can be designed by transferring a binding motif on a protein host selected to reproduce the functional topology of this motif, irrespective to the secondary structure supporting the functional motif, if the host protein possesses steric and electrostatic properties compatible with the binding to the target. This result opens the way to the design of protein ligands by taking advantage of the considerable structural repertoire of the Protein Data Bank. [ABSTRACT FROM AUTHOR] |
| Copyright of Journal of the American Chemical Society is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Header | DbId: egs DbLabel: Engineering Source An: 23545693 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Structure-Based Secondary Structure-Independent Approach To Design Protein Ligands: Application to the Design of Kv1.2 Potassium Channel Blockers. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Magis%2C+C%2E%22">Magis, C.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Gasparini%2C+D%2E%22">Gasparini, D.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Lecoq%2C+A%2E%22">Lecoq, A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Le+Du%2C+M%2E+H%2E%22">Le Du, M. H.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Stura%2C+E%2E%22">Stura, E.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Charbonnier%2C+J%2E+B%2E%22">Charbonnier, J. B.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Mourier%2C+G%2E%22">Mourier, G.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Boulain%2C+J%2E-C%2E%22">Boulain, J.-C.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Pardo%2C+L%2E%22">Pardo, L.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Caruana%2C+A%2E%22">Caruana, A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Joly%2C+A%2E%22">Joly, A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Lefranc%2C+M%2E%22">Lefranc, M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Masella%2C+M%2E%22">Masella, M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Menez%2C+A%2E%22">Menez, A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Cuniasse%2C+P%2E%22">Cuniasse, P.</searchLink><relatesTo>1</relatesTo><i> philippe.cuniasse@cea.fr</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Journal+of+the+American+Chemical+Society%22">Journal of the American Chemical Society</searchLink>. 12/20/2006, Vol. 128 Issue 50, p16190-16205. 16p. 1 Diagram, 7 Charts. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Protein+engineering%22">Protein engineering</searchLink><br /><searchLink fieldCode="DE" term="%22Ligand+binding+%28Biochemistry%29%22">Ligand binding (Biochemistry)</searchLink><br /><searchLink fieldCode="DE" term="%22Radioligand+assay%22">Radioligand assay</searchLink><br /><searchLink fieldCode="DE" term="%22Ligands+%28Chemistry%29%22">Ligands (Chemistry)</searchLink><br /><searchLink fieldCode="DE" term="%22Potassium+channels%22">Potassium channels</searchLink><br /><searchLink fieldCode="DE" term="%22Topology%22">Topology</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: We have developed a structure-based approach to the design of protein ligands. This approach is based on the transfer of a functional binding motif of amino acids, often referred as to the ‘hot spot’, on a host protein able to reproduce the functional topology of these residues. The scaffolds were identified by a systematic in silico search in the Protein Data Bank for proteins possessing a group of residues in a topology similar to that adopted by the functional motif in a reference ligand of known 3D structure. In contrast to previously reported studies, this search is independent of the particular secondary structure supporting the functional motif. To take into account the global properties of the host protein, two additional criteria were taken into account in the selection process: (1) Only those scaffolds sterically compatible with the positioning of the functional motif as observed in a reference complex model were retained. (2) Host proteins displaying electrostatic potentials, in the region of the transferred functional motif, similar to that of the reference ligand were selected. This approach was applied to the development of protein ligands of the Kvl .2 channel using BgK, a small protein isolated from the sea anemone Bunodosoma granulifera, as the reference ligand. Four proteins obtained by this approach were produced for experimental evaluation. The X-ray structure of one of these proteins was determined to check for similarity of the transferred functional motif with the structure it adopts in the reference ligand. Three of these protein ligands bind the Kvl .2 channel with inhibition constants of 0.5, 1.5, and 1.6 μM. Several mutants of these designed protein ligands gave binding results consistent with the presumed binding mode. These results show that protein ligands can be designed by transferring a binding motif on a protein host selected to reproduce the functional topology of this motif, irrespective to the secondary structure supporting the functional motif, if the host protein possesses steric and electrostatic properties compatible with the binding to the target. This result opens the way to the design of protein ligands by taking advantage of the considerable structural repertoire of the Protein Data Bank. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Journal of the American Chemical Society is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1021/ja0646491 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 16 StartPage: 16190 Subjects: – SubjectFull: Protein engineering Type: general – SubjectFull: Ligand binding (Biochemistry) Type: general – SubjectFull: Radioligand assay Type: general – SubjectFull: Ligands (Chemistry) Type: general – SubjectFull: Potassium channels Type: general – SubjectFull: Topology Type: general Titles: – TitleFull: Structure-Based Secondary Structure-Independent Approach To Design Protein Ligands: Application to the Design of Kv1.2 Potassium Channel Blockers. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Magis, C. – PersonEntity: Name: NameFull: Gasparini, D. – PersonEntity: Name: NameFull: Lecoq, A. – PersonEntity: Name: NameFull: Le Du, M. H. – PersonEntity: Name: NameFull: Stura, E. – PersonEntity: Name: NameFull: Charbonnier, J. B. – PersonEntity: Name: NameFull: Mourier, G. – PersonEntity: Name: NameFull: Boulain, J.-C. – PersonEntity: Name: NameFull: Pardo, L. – PersonEntity: Name: NameFull: Caruana, A. – PersonEntity: Name: NameFull: Joly, A. – PersonEntity: Name: NameFull: Lefranc, M. – PersonEntity: Name: NameFull: Masella, M. – PersonEntity: Name: NameFull: Menez, A. – PersonEntity: Name: NameFull: Cuniasse, P. IsPartOfRelationships: – BibEntity: Dates: – D: 20 M: 12 Text: 12/20/2006 Type: published Y: 2006 Identifiers: – Type: issn-print Value: 00027863 Numbering: – Type: volume Value: 128 – Type: issue Value: 50 Titles: – TitleFull: Journal of the American Chemical Society Type: main |
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