A Carrier Protein Strategy Yields the Structure of Dalbavancin.
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| Title: | A Carrier Protein Strategy Yields the Structure of Dalbavancin. |
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| Authors: | Economou, Nicoleta J.1, Nahoum, Virginie2, Weeks, Stephen D.3, Grasty, Kimberly C.1, Zentner, Isaac J.1, Townsend, Tracy M.4, Bhuiya, Mohammad W.5, Cocklin, Simon1, Loll, Patrick J.1 ploll@drexelmed.edu |
| Source: | Journal of the American Chemical Society. 3/14/2012, Vol. 134 Issue 10, p4637-4645. 9p. |
| Subjects: | Carrier proteins, Biochemistry experiments, Biochemistry methodology, Structural analysis (Science), Ligation reactions |
| Abstract: | Many large natural product antibiotics act by specifically binding and sequestering target molecules found on bacterial cells. We have developed a new strategy to expedite the structural analysis of such antibiotic-target complexes, in which we covalently link the target molecules to carrier proteins, and then crystallize the entire carrier-target-antibiotic complex. Using native chemical ligation, we have linked the Lys-d-Ala-d-Ala binding epitope for glycopeptide antibiotics to three different carrier proteins. We show that recognition of this peptide by multiple antibiotics is not compromised by the presence of the carrier protein partner, and use this approach to determine the first-ever crystal structure for the new therapeutic dalbavancin. We also report the first crystal structure of an asymmetric ristocetin antibiotic dimer, as well as the structure of vancomycin bound to a carrier-target fusion. The dalbavancin structure reveals an antibiotic molecule that has closed around its binding partner; it also suggests mechanisms by which the drug can enhance its half-life by binding to serum proteins, and be targeted to bacterial membranes. Notably, the carrier protein approach is not limited to peptide ligands such as Lys-d-Ala-d-Ala, but is applicable to a diverse range of targets. This strategy is likely to yield structural insights that accelerate new therapeutic development. [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: 74011123 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: A Carrier Protein Strategy Yields the Structure of Dalbavancin. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Economou%2C+Nicoleta+J%2E%22">Economou, Nicoleta J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Nahoum%2C+Virginie%22">Nahoum, Virginie</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Weeks%2C+Stephen+D%2E%22">Weeks, Stephen D.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Grasty%2C+Kimberly+C%2E%22">Grasty, Kimberly C.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Zentner%2C+Isaac+J%2E%22">Zentner, Isaac J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Townsend%2C+Tracy+M%2E%22">Townsend, Tracy M.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Bhuiya%2C+Mohammad+W%2E%22">Bhuiya, Mohammad W.</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Cocklin%2C+Simon%22">Cocklin, Simon</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Loll%2C+Patrick+J%2E%22">Loll, Patrick J.</searchLink><relatesTo>1</relatesTo><i> ploll@drexelmed.edu</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>. 3/14/2012, Vol. 134 Issue 10, p4637-4645. 9p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Carrier+proteins%22">Carrier proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Biochemistry+experiments%22">Biochemistry experiments</searchLink><br /><searchLink fieldCode="DE" term="%22Biochemistry+methodology%22">Biochemistry methodology</searchLink><br /><searchLink fieldCode="DE" term="%22Structural+analysis+%28Science%29%22">Structural analysis (Science)</searchLink><br /><searchLink fieldCode="DE" term="%22Ligation+reactions%22">Ligation reactions</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Many large natural product antibiotics act by specifically binding and sequestering target molecules found on bacterial cells. We have developed a new strategy to expedite the structural analysis of such antibiotic-target complexes, in which we covalently link the target molecules to carrier proteins, and then crystallize the entire carrier-target-antibiotic complex. Using native chemical ligation, we have linked the Lys-d-Ala-d-Ala binding epitope for glycopeptide antibiotics to three different carrier proteins. We show that recognition of this peptide by multiple antibiotics is not compromised by the presence of the carrier protein partner, and use this approach to determine the first-ever crystal structure for the new therapeutic dalbavancin. We also report the first crystal structure of an asymmetric ristocetin antibiotic dimer, as well as the structure of vancomycin bound to a carrier-target fusion. The dalbavancin structure reveals an antibiotic molecule that has closed around its binding partner; it also suggests mechanisms by which the drug can enhance its half-life by binding to serum proteins, and be targeted to bacterial membranes. Notably, the carrier protein approach is not limited to peptide ligands such as Lys-d-Ala-d-Ala, but is applicable to a diverse range of targets. This strategy is likely to yield structural insights that accelerate new therapeutic development. [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/ja208755j Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 9 StartPage: 4637 Subjects: – SubjectFull: Carrier proteins Type: general – SubjectFull: Biochemistry experiments Type: general – SubjectFull: Biochemistry methodology Type: general – SubjectFull: Structural analysis (Science) Type: general – SubjectFull: Ligation reactions Type: general Titles: – TitleFull: A Carrier Protein Strategy Yields the Structure of Dalbavancin. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Economou, Nicoleta J. – PersonEntity: Name: NameFull: Nahoum, Virginie – PersonEntity: Name: NameFull: Weeks, Stephen D. – PersonEntity: Name: NameFull: Grasty, Kimberly C. – PersonEntity: Name: NameFull: Zentner, Isaac J. – PersonEntity: Name: NameFull: Townsend, Tracy M. – PersonEntity: Name: NameFull: Bhuiya, Mohammad W. – PersonEntity: Name: NameFull: Cocklin, Simon – PersonEntity: Name: NameFull: Loll, Patrick J. IsPartOfRelationships: – BibEntity: Dates: – D: 14 M: 03 Text: 3/14/2012 Type: published Y: 2012 Identifiers: – Type: issn-print Value: 00027863 Numbering: – Type: volume Value: 134 – Type: issue Value: 10 Titles: – TitleFull: Journal of the American Chemical Society Type: main |
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