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3RUL

New strategy to analyze structures of glycopeptide-target complexes

Summary for 3RUL
Entry DOI10.2210/pdb3rul/pdb
Related3A9J 3RUM 3RUN
DescriptorUbiquitin, Dalbavancin, L(+)-TARTARIC ACID, ... (8 entities in total)
Functional Keywordsantibiotic, glycopeptide, native protein ligation, fusion, carboxymethylation of cysteine, dalbavancin, signaling protein-antibiotic complex, signaling protein/antibiotic
Biological sourceHomo sapiens (human)
Cellular locationUbiquitin: Cytoplasm (By similarity): P0CG48
Total number of polymer chains8
Total formula weight43896.19
Authors
Economou, N.J.,Nahoum, V.,Weeks, S.D.,Grasty, K.C.,Loll, P.J. (deposition date: 2011-05-05, release date: 2012-06-06, Last modification date: 2023-12-06)
Primary citationEconomou, N.J.,Nahoum, V.,Weeks, S.D.,Grasty, K.C.,Zentner, I.J.,Townsend, T.M.,Bhuiya, M.W.,Cocklin, S.,Loll, P.J.
A carrier protein strategy yields the structure of dalbavancin.
J.Am.Chem.Soc., 134:4637-4645, 2012
Cited by
PubMed 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.
PubMed: 22352468
DOI: 10.1021/ja208755j
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.5 Å)
Structure validation

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