1PPW: ISOPENTENYLPYROPHOSPHATE-DIMETHYLALLYLPYROPHOSPHATE ISOMERASE IN COMPLEX WITH THE BROMOHYDRINE OF IPP

Citation:
Abstract
We report the crystallographic structures of the potent phosphoantigens Phosphostim (the bromohydrin of isopentenyl pyrophosphate) and E-4-hydroxy-3-methyl-but-2-enyl pyrophosphate bound to the mevalonate pathway enzyme isopentenyl pyrophosphate/dimethylallyl pyrophosphate isomerase (IPPI). Racemic Phosphostim forms covalent complexes with IPPI: a 4-thioether with C67 and a 4-ester with E116. Only the E116 ester forms with the chiral species, S-Phosphostim, with the w.t. enzyme, while the C67 thioether forms with a mutant Y104F IPPI. The potent phosphoantigen HMBPP also binds to IPPI, but is only a weak ( approximately 50 muM) inhibitor. These results strongly support an SN2 reaction for inhibition of IPPI by Phosphostim, in contrast to the SN1 or concerted type of reaction found with epoxide inhibitors, which react at C-3, and are of general interest in the context of the development of novel mevalonate pathway inhibitors. They also provide clues as to the nature of the binding site of synthetic phosphoantigens in gammadelta T cell activation. In particular, both bromohydrin and epoxy phosphoantigens are potent, irreversible inhibitors of IPPI while HMBPP is only a weak inhibitor, ruling out an IPPI or IPPI-like target for HMBPP in gammadelta T cell activation.
PDB ID: 1PPWDownload
MMDB ID: 28147
PDB Deposition Date: 2003/6/17
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.21  Å
Source Organism:
Similar Structures:
Biological Unit for 1PPW: dimeric; determined by author and by software (PISA)
Molecular Components in 1PPW
Label Count Molecule
Proteins (2 molecules)
2
Isopentenyl-diphosphate Delta-isomerase(Gene symbol: idi)
Molecule annotation
Chemicals (6 molecules)
1
2
2
2
3
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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