1x83
From Proteopedia
(New page: 200px<br /><applet load="1x83" size="450" color="white" frame="true" align="right" spinBox="true" caption="1x83, resolution 1.8Å" /> '''Y104F IPP isomerase r...) |
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| - | [[Image:1x83.gif|left|200px]]<br /><applet load="1x83" size=" | + | [[Image:1x83.gif|left|200px]]<br /><applet load="1x83" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1x83, resolution 1.8Å" /> | caption="1x83, resolution 1.8Å" /> | ||
'''Y104F IPP isomerase reacted with (S)-bromohydrine of IPP'''<br /> | '''Y104F IPP isomerase reacted with (S)-bromohydrine of IPP'''<br /> | ||
==Overview== | ==Overview== | ||
| - | 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 ( | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 1X83 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with MN, MG and SBH as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Isopentenyl-diphosphate_Delta-isomerase Isopentenyl-diphosphate Delta-isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.3.2 5.3.3.2] Full crystallographic information is available from [http:// | + | 1X83 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=MN:'>MN</scene>, <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=SBH:'>SBH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Isopentenyl-diphosphate_Delta-isomerase Isopentenyl-diphosphate Delta-isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.3.2 5.3.3.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1X83 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: isomerase]] | [[Category: isomerase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:51:57 2008'' |
Revision as of 13:51, 21 February 2008
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Y104F IPP isomerase reacted with (S)-bromohydrine of IPP
Overview
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.
About this Structure
1X83 is a Single protein structure of sequence from Escherichia coli with , and as ligands. Active as Isopentenyl-diphosphate Delta-isomerase, with EC number 5.3.3.2 Full crystallographic information is available from OCA.
Reference
A crystallographic investigation of phosphoantigen binding to isopentenyl pyrophosphate/dimethylallyl pyrophosphate isomerase., Wouters J, Yin F, Song Y, Zhang Y, Oudjama Y, Stalon V, Droogmans L, Morita CT, Oldfield E, J Am Chem Soc. 2005 Jan 19;127(2):536-7. PMID:15643873
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