Crystal and molecular structure of didemnin B, an antiviral and cytotoxic depsipeptide.

Hossain, M. B.; Helm, D. van der; Antel, Jack P.; Sheldrick, George M.; Sanduja, Sudershan K.; Weinheimer, Alfred J.

doi:10.1073/pnas.85.12.4118

Cited by 71 publications

(72 citation statements)

References 11 publications

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“…Both NMR 33 and X-ray diffraction 34 studies have shown a highly asymmetric shape for DB, with the macrocycle resembling a twisted figure "8" (Figure 4). The six residues making up the depsipeptide ring structure (isostatine (Ist 1 ), 2-(R-hydroxyisovaleryl) propionate (Hip 2 ), leucine (Leu 3 ), proline (Pro 4 ), N,Odimethyltyrosine (Me 2 Tyr 5 ), and threonine (Thr 6 )) have the L configuration, whereas the linear peptide attached to this latter amino acid contains N-methyl-D-leucine (MeLeu 7 ) and lactylproline (Pro 8 -Lac 9 ).…”

Section: Resultsmentioning

confidence: 99%

“…The six residues making up the depsipeptide ring structure (isostatine (Ist 1 ), 2-(R-hydroxyisovaleryl) propionate (Hip 2 ), leucine (Leu 3 ), proline (Pro 4 ), N,Odimethyltyrosine (Me 2 Tyr 5 ), and threonine (Thr 6 )) have the L configuration, whereas the linear peptide attached to this latter amino acid contains N-methyl-D-leucine (MeLeu 7 ) and lactylproline (Pro 8 -Lac 9 ). 2,34 The only transannular hydrogen bond (Ist 1 -NH‚‚‚OdC-Leu 3 ) that has been described in these experimental structures of DB, as well as in the crystal structure of DA 35 and in the solution structure of dehydrodidemnin B (aplidine), 36 is maintained during the MD simulations in water, as is the Leu 3 -NH‚‚‚OdC-MeLeu 7 hydrogen bond that binds the linear chain to the cyclic backbone. In contrast, the hydrogen bond established within the linear part of DB (Thr 6 -NH‚‚‚OdC-Lac 9 ) is overtly disrupted by competing interactions with water molecules (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…This latter interaction implies disruption of the intramolecular hydrogen bond that stabilizes the conventional -II turn described for both DB in the solid state 34 and dehydrodidemnin B in CDCl 3 solution, 36 even though it has been shown to be unnecessary for bioactivity. 2 This model for DB binding to eEF1A strongly suggests that this natural compound stabilizes the interface between domains 1 and 2 of this elongation factor in the GTP conformation when it is bound to the ribosome just after delivery of the aa-tRNA.…”

Section: Discussionmentioning

confidence: 99%

“…The X-ray crystal structure of DB 34 was used in the construction of the initial model. Electrostatic potential-derived charges for the nonstandard residues in DB, as well as for GTP‚Mg 2+ , were obtained with the RESP methodology 75 using a 6-31G* basis set as implemented in the Gaussian 98 program.…”

Section: Methodsmentioning

confidence: 99%

“…Side-by-side comparison of (a) the tertiary structures of the 2-3 loop of eEF1BR containing Phe163 and (b) the X-ray crystal structure of DB. 34 For comparison purposes, the sequences of the yeast eEF1BR (black) and human eEF1BR and eEF1BR (red) hairpins are shown. domain 2 of eEF1A could provide a docking site to this DB's protrusion.…”

Section: Introductionmentioning

confidence: 99%

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Structural Basis for the Binding of Didemnins to Human Elongation Factor eEF1A and Rationale for the Potent Antitumor Activity of These Marine Natural Products

et al. 2004

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Didemnins and tamandarins are closely related marine natural products with potent inhibitory effects on protein synthesis and cell viability. On the basis of available biochemical and structural evidence and results from molecular dynamics simulations, a model is proposed that accounts for the strong and selective binding of these compounds to human elongation factor eEF1A in the presence of GTP. We suggest that the p-methoxyphenyl ring of these cyclic depsipeptides is inserted into the same pocket in eEF1A that normally lodges either the 3′ terminal adenine of aminoacylated tRNA, as inferred from two prokaryotic EF-Tu‚GTP‚tRNA complexes, or the aromatic side chain of Phe/Tyr-163 from the nucleotide exchange factor eEF1BR, as observed in several X-ray crystal structures of a yeast eEF1A:eEF1BR complex. This pocket, which has a strong hydrophobic character, is formed by two protruding loops on the surface of eEF1A domain 2. Further stabilization of the bound depsipeptide is brought about by additional crucial interactions involving eEF1A domain 1 in such a way that the molecule fits snugly at the interface between these two domains. In the GDP-bound form of eEF1A, this binding site exists only as two separate halves, which accounts for the much greater affinity of didemnins for the GTP-bound form of this elongation factor. This binding mode is entirely different from those seen in the complexes of the homologous prokaryotic EF-Tu with kirromycin-type antibiotics or the cyclic thiazolyl peptide antibiotic GE2270A. Interestingly, the set of interactions used by didemnins to bind to eEF1A is also distinct from that used by eEF1BR or eEF1B , thus establishing a competition for binding to a common site that goes beyond simple molecular mimicry. The model presented here is consistent with both available biochemical evidence and known structure-activity relationships for these two classes of natural compounds and synthetic analogues and provides fertile ground for future research.

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Section: Resultsmentioning

confidence: 99%