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Crystal structure of CdpNPT in its unbound stateCrystal structure of CdpNPT in its unbound state
Structural highlights
Publication Abstract from PubMedFungal indole prenyltransferases (PTs) typically act on specific substrates, and they are able to prenylate their target compounds with remarkably high regio- and stereoselectivity. Similar to several indole PTs characterized to date, the cyclic dipeptide N-prenyltransferase (CdpNPT) is able to prenylate a range of diverse substrates, thus exhibiting an unusually broad substrate promiscuity. To define the structural basis for this promiscuity, we have determined crystal structures of unliganded CdpNPT and of a ternary complex of CdpNPT bound to (S)-benzodiazepinedione and thiolodiphosphate. Analysis of the structures reveals a limited number of specific interactions with (S)-benzodiazepinedione, which projects into a largely hydrophobic surface. This surface can also accommodate other substrates, explaining the ability of the enzyme to prenylate a range of compounds. The location of the bound substrates suggests a likely reaction mechanism for the conversion of (S)-benzodiazepinedione. Structure-guided mutagenesis experiments confirm that, in addition to (S)-benzodiazepinedione, CdpNPT can also act on (R)-benzodiazepinedione and several cyclic dipeptides, albeit with relaxed specificity. Finally, nuclear magnetic resonance spectroscopy demonstrates that CdpNPT is a C-3 reverse PT that catalyzes the formation of C-3beta prenylated indolines from diketopiperazines of tryptophan-containing cyclic dipeptides. Structure and catalytic mechanism of a cyclic dipeptide prenyltransferase with broad substrate promiscuity.,Schuller JM, Zocher G, Liebhold M, Xie X, Stahl M, Li SM, Stehle T J Mol Biol. 2012 Sep 7;422(1):87-99. Epub 2012 Jun 6. PMID:22683356[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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