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| | {{STRUCTURE_1d8t| PDB=1d8t | SCENE= }} | | {{STRUCTURE_1d8t| PDB=1d8t | SCENE= }} |
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| - | '''CRYSTAL STRUCTURE OF ELONGATION FACTOR, TU (EF-TU-MGGDP) COMPLEXED WITH GE2270A, A THIAZOLYL PEPTIDE ANTIBIOTIC'''
| + | ===CRYSTAL STRUCTURE OF ELONGATION FACTOR, TU (EF-TU-MGGDP) COMPLEXED WITH GE2270A, A THIAZOLYL PEPTIDE ANTIBIOTIC=== |
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| - | ==Overview==
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| - | The structure of a 1:1 molar complex between Escherichia coli elongation factor (EF) Tu-GDP and the cyclic thiazolyl peptide antibiotic, GE2270A, has been determined by X-ray diffraction analysis to a resolution of 2.35 A and refined to a crystallographic refinement factor of 20.6%. The antibiotic binds in the second domain of EF-Tu-GDP, making contact with three segments of amino acids (residues 215-230, 256-264, and 273-277). The majority of the protein-antibiotic contacts are van der Waals interactions. A striking feature of the antibiotic binding site is the presence of a salt bridge, not previously observed in other EF-Tu complexes. The ionic interaction between Arg 223 and Glu 259 forms over the antibiotic and probably accounts for the strong affinity observed between EF-Tu and GE2270A. Arg 223 and Glu 259 are highly conserved, but not invariant throughout the prokaryotic EF-Tu family, suggesting that the antibiotic may bind EF-Tu from some organisms better than others may. Superposition of the antibiotic binding site on the EF-Tu-GTP conformation reveals that one region of the antibiotic would form steric clashes with the guanine nucleotide-binding domain in the GTP, but not the GDP, conformation. Another region of the antibiotic binds to the same site as the aminoacyl group of tRNA. Together with prior biochemical studies, the structural findings confirm that GE2270A inhibits protein synthesis by blocking the GDP to GTP conformational change and by directly competing with aminoacyl-tRNA for the same binding site on EF-Tu. In each of the bacterial strains that are resistant to GE2270A, the effect of a site-specific mutation in EF-Tu could explain resistance. Comparison of the GE2270A site in EF-Tu with sequence homologues, EF-G and EF-1alpha, suggests steric clashes that would prevent the antibiotic from binding to translocation factors or to the eukaryotic equivalent of EF-Tu. Although GE2270A is a potent antibiotic, its clinical efficacy is limited by its low aqueous solubility. The results presented here provide the details necessary to enhance the solubility of GE2270A without disrupting its inhibitory properties.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10625477}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10625477 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_10625477}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Protein-antibiotic complex]] | | [[Category: Protein-antibiotic complex]] |
| | [[Category: Trna-binding]] | | [[Category: Trna-binding]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 13:34:41 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 22:40:53 2008'' |
Revision as of 19:40, 30 June 2008
Template:STRUCTURE 1d8t
CRYSTAL STRUCTURE OF ELONGATION FACTOR, TU (EF-TU-MGGDP) COMPLEXED WITH GE2270A, A THIAZOLYL PEPTIDE ANTIBIOTIC
Template:ABSTRACT PUBMED 10625477
About this Structure
1D8T is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
Reference
Structure of an EF-Tu complex with a thiazolyl peptide antibiotic determined at 2.35 A resolution: atomic basis for GE2270A inhibition of EF-Tu., Heffron SE, Jurnak F, Biochemistry. 2000 Jan 11;39(1):37-45. PMID:10625477
Page seeded by OCA on Mon Jun 30 22:40:53 2008
