3b6h
From Proteopedia
(New page: 200px<br /><applet load="3b6h" size="350" color="white" frame="true" align="right" spinBox="true" caption="3b6h, resolution 1.62Å" /> '''Crystal structure of...) |
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caption="3b6h, resolution 1.62Å" /> | caption="3b6h, resolution 1.62Å" /> | ||
'''Crystal structure of human prostacyclin synthase in complex with inhibitor minoxidil'''<br /> | '''Crystal structure of human prostacyclin synthase in complex with inhibitor minoxidil'''<br /> | ||
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| + | ==Overview== | ||
| + | Prostacyclin synthase (PGIS) is a cytochrome P450 (P450) enzyme that, catalyzes production of prostacyclin from prostaglandin H(2). PGIS is, unusual in that it catalyzes an isomerization rather than a, monooxygenation, which is typical of P450 enzymes. To understand the, structural basis for prostacyclin biosynthesis in greater detail, we have, determined the crystal structures of ligand-free, inhibitor, (minoxidil)-bound and substrate analog U51605-bound PGIS. These structures, demonstrate a stereo-specific substrate binding and suggest features of, the enzyme that facilitate isomerization. Unlike most microsomal P450s, where large substrate-induced conformational changes take place at the, distal side of the heme, conformational changes in PGIS are observed at, the proximal side and in the heme itself. The conserved and extensive heme, propionate-protein interactions seen in all other P450s, which are largely, absent in the ligand-free PGIS, are recovered upon U51605 binding, accompanied by water exclusion from the active site. In contrast, when, minoxidil binds, the propionate-protein interactions are not recovered and, water molecules are largely retained. These findings suggest that PGIS, represents a divergent evolution of the P450 family, in which a heme, barrier has evolved to ensure strict binding specificity for prostaglandin, H(2), leading to a radical-mediated isomerization with high product, fidelity. The U51605-bound structure also provides a view of the substrate, entrance and product exit channels. | ||
==About this Structure== | ==About this Structure== | ||
| - | 3B6H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=BOG:'>BOG</scene>, <scene name='pdbligand=MXD:'>MXD</scene> and <scene name='pdbligand=HEM:'>HEM</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Prostaglandin-I_synthase Prostaglandin-I synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.99.4 5.3.99.4] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3B6H OCA]. | + | 3B6H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=BOG:'>BOG</scene>, <scene name='pdbligand=MXD:'>MXD</scene> and <scene name='pdbligand=HEM:'>HEM</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Prostaglandin-I_synthase Prostaglandin-I synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.99.4 5.3.99.4] Known structural/functional Sites: <scene name='pdbsite=AC1:Bog+Binding+Site+For+Residue+A+701'>AC1</scene>, <scene name='pdbsite=AC2:Bog+Binding+Site+For+Residue+B+702'>AC2</scene>, <scene name='pdbsite=AC3:Mxd+Binding+Site+For+Residue+A+551'>AC3</scene>, <scene name='pdbsite=AC4:Hem+Binding+Site+For+Residue+A+600'>AC4</scene>, <scene name='pdbsite=AC5:Mxd+Binding+Site+For+Residue+B+551'>AC5</scene> and <scene name='pdbsite=AC6:Hem+Binding+Site+For+Residue+B+600'>AC6</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3B6H OCA]. |
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| + | ==Reference== | ||
| + | Structures of Prostacyclin Synthase and Its Complexes with Substrate Analog and Inhibitor Reveal a Ligand-specific Heme Conformation Change., Li YC, Chiang CW, Yeh HC, Hsu PY, Whitby FG, Wang LH, Chan NL, J Biol Chem. 2008 Feb 1;283(5):2917-26. Epub 2007 Nov 21. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18032380 18032380] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Prostaglandin-I synthase]] | [[Category: Prostaglandin-I synthase]] | ||
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[[Category: transmembrane]] | [[Category: transmembrane]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 13 08:18:45 2008'' |
Revision as of 06:18, 13 February 2008
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Crystal structure of human prostacyclin synthase in complex with inhibitor minoxidil
Overview
Prostacyclin synthase (PGIS) is a cytochrome P450 (P450) enzyme that, catalyzes production of prostacyclin from prostaglandin H(2). PGIS is, unusual in that it catalyzes an isomerization rather than a, monooxygenation, which is typical of P450 enzymes. To understand the, structural basis for prostacyclin biosynthesis in greater detail, we have, determined the crystal structures of ligand-free, inhibitor, (minoxidil)-bound and substrate analog U51605-bound PGIS. These structures, demonstrate a stereo-specific substrate binding and suggest features of, the enzyme that facilitate isomerization. Unlike most microsomal P450s, where large substrate-induced conformational changes take place at the, distal side of the heme, conformational changes in PGIS are observed at, the proximal side and in the heme itself. The conserved and extensive heme, propionate-protein interactions seen in all other P450s, which are largely, absent in the ligand-free PGIS, are recovered upon U51605 binding, accompanied by water exclusion from the active site. In contrast, when, minoxidil binds, the propionate-protein interactions are not recovered and, water molecules are largely retained. These findings suggest that PGIS, represents a divergent evolution of the P450 family, in which a heme, barrier has evolved to ensure strict binding specificity for prostaglandin, H(2), leading to a radical-mediated isomerization with high product, fidelity. The U51605-bound structure also provides a view of the substrate, entrance and product exit channels.
About this Structure
3B6H is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Prostaglandin-I synthase, with EC number 5.3.99.4 Known structural/functional Sites: , , , , and . Full crystallographic information is available from OCA.
Reference
Structures of Prostacyclin Synthase and Its Complexes with Substrate Analog and Inhibitor Reveal a Ligand-specific Heme Conformation Change., Li YC, Chiang CW, Yeh HC, Hsu PY, Whitby FG, Wang LH, Chan NL, J Biol Chem. 2008 Feb 1;283(5):2917-26. Epub 2007 Nov 21. PMID:18032380
Page seeded by OCA on Wed Feb 13 08:18:45 2008
Categories: Homo sapiens | Prostaglandin-I synthase | Single protein | Chan, N.L. | Chiang, C.W. | Hsu, P.Y. | Li, Y.C. | Wang, L.H. | Whitby, F.G. | Yeh, H.C. | BOG | HEM | MXD | Cyp8a1 | Cytochrome p450 | Endoplasmic reticulum | Enzyme-inhibitor complex | Fatty acid biosynthesis | Heme | Iron | Isomerase | Lipid synthesis | Membrane | Metal-binding | Polymorphism | Prostacyclin synthase | Prostaglandin biosynthesis | Transmembrane
