1zef
From Proteopedia
(New page: 200px<br /> <applet load="1zef" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zef, resolution 1.90Å" /> '''structure of alkali...) |
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| - | [[Image:1zef.gif|left|200px]]<br /> | + | [[Image:1zef.gif|left|200px]]<br /><applet load="1zef" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1zef" size=" | + | |
caption="1zef, resolution 1.90Å" /> | caption="1zef, resolution 1.90Å" /> | ||
'''structure of alkaline phosphatase from human placenta in complex with its uncompetitive inhibitor L-Phe'''<br /> | '''structure of alkaline phosphatase from human placenta in complex with its uncompetitive inhibitor L-Phe'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The activity of human placental alkaline phosphatase (PLAP) is | + | The activity of human placental alkaline phosphatase (PLAP) is downregulated by a number of effectors such as l-phenylalanine, an uncompetitive inhibitor, 5'-AMP, an antagonist of the effects of PLAP on fibroblast proliferation and by p-nitrophenyl-phosphonate (PNPPate), a non-hydrolysable substrate analogue. For the first two, such regulation may be linked to its biological function that requires a reduced and better-regulated hydrolytic rate. To understand how such disparate ligands are able to inhibit the enzyme, we solved the structure of the complexes at 1.6A, 1.9A and 1.9A resolution, respectively. These crystal structures are the first of an alkaline phosphatase in complex with organic inhibitors. Of the three inhibitors, only l-Phe and PNPPate bind at the active site hydrophobic pocket, providing structural data on the uncompetitive inhibition process. In contrast, all three ligands interact at a remote peripheral site located 28A from the active site. In order to extend these observations to the other members of the human alkaline phosphatase family, we have modelled the structures of the other human isozymes and compared them to PLAP. This comparison highlights the crucial role played by position 429 at the active site in the modulation of the catalytic process, and suggests that the peripheral binding site may be involved in the functional specialization of the PLAP isozyme. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1ZEF 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 NAG, PO3, ZN, MG, CA and PHE as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Alkaline_phosphatase Alkaline phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.1 3.1.3.1] Full crystallographic information is available from [http:// | + | 1ZEF 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=NAG:'>NAG</scene>, <scene name='pdbligand=PO3:'>PO3</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=PHE:'>PHE</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Alkaline_phosphatase Alkaline phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.1 3.1.3.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZEF OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Du, M | + | [[Category: Du, M H.Le.]] |
[[Category: Kiss, Z.]] | [[Category: Kiss, Z.]] | ||
[[Category: Llinas, P.]] | [[Category: Llinas, P.]] | ||
[[Category: Menez, A.]] | [[Category: Menez, A.]] | ||
| - | [[Category: Millan, J | + | [[Category: Millan, J L.]] |
[[Category: Stigbrand, T.]] | [[Category: Stigbrand, T.]] | ||
| - | [[Category: Stura, E | + | [[Category: Stura, E A.]] |
[[Category: CA]] | [[Category: CA]] | ||
[[Category: MG]] | [[Category: MG]] | ||
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[[Category: uncompetitive inhibitor]] | [[Category: uncompetitive inhibitor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:14:43 2008'' |
Revision as of 14:14, 21 February 2008
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structure of alkaline phosphatase from human placenta in complex with its uncompetitive inhibitor L-Phe
Contents |
Overview
The activity of human placental alkaline phosphatase (PLAP) is downregulated by a number of effectors such as l-phenylalanine, an uncompetitive inhibitor, 5'-AMP, an antagonist of the effects of PLAP on fibroblast proliferation and by p-nitrophenyl-phosphonate (PNPPate), a non-hydrolysable substrate analogue. For the first two, such regulation may be linked to its biological function that requires a reduced and better-regulated hydrolytic rate. To understand how such disparate ligands are able to inhibit the enzyme, we solved the structure of the complexes at 1.6A, 1.9A and 1.9A resolution, respectively. These crystal structures are the first of an alkaline phosphatase in complex with organic inhibitors. Of the three inhibitors, only l-Phe and PNPPate bind at the active site hydrophobic pocket, providing structural data on the uncompetitive inhibition process. In contrast, all three ligands interact at a remote peripheral site located 28A from the active site. In order to extend these observations to the other members of the human alkaline phosphatase family, we have modelled the structures of the other human isozymes and compared them to PLAP. This comparison highlights the crucial role played by position 429 at the active site in the modulation of the catalytic process, and suggests that the peripheral binding site may be involved in the functional specialization of the PLAP isozyme.
Disease
Known disease associated with this structure: Osteoarthritis, susceptibility to OMIM:[608135]
About this Structure
1ZEF is a Single protein structure of sequence from Homo sapiens with , , , , and as ligands. Active as Alkaline phosphatase, with EC number 3.1.3.1 Full crystallographic information is available from OCA.
Reference
Structural studies of human placental alkaline phosphatase in complex with functional ligands., Llinas P, Stura EA, Menez A, Kiss Z, Stigbrand T, Millan JL, Le Du MH, J Mol Biol. 2005 Jul 15;350(3):441-51. PMID:15946677
Page seeded by OCA on Thu Feb 21 16:14:43 2008
Categories: Alkaline phosphatase | Homo sapiens | Single protein | Du, M H.Le. | Kiss, Z. | Llinas, P. | Menez, A. | Millan, J L. | Stigbrand, T. | Stura, E A. | CA | MG | NAG | PHE | PO3 | ZN | Intermediate state | L-phe | Uncompetitive inhibitor
