1hv5
From Proteopedia
(New page: 200px<br /><applet load="1hv5" size="450" color="white" frame="true" align="right" spinBox="true" caption="1hv5, resolution 2.60Å" /> '''CRYSTAL STRUCTURE OF...) |
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| - | [[Image:1hv5.gif|left|200px]]<br /><applet load="1hv5" size=" | + | [[Image:1hv5.gif|left|200px]]<br /><applet load="1hv5" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1hv5, resolution 2.60Å" /> | caption="1hv5, resolution 2.60Å" /> | ||
'''CRYSTAL STRUCTURE OF THE STROMELYSIN-3 (MMP-11) CATALYTIC DOMAIN COMPLEXED WITH A PHOSPHINIC INHIBITOR'''<br /> | '''CRYSTAL STRUCTURE OF THE STROMELYSIN-3 (MMP-11) CATALYTIC DOMAIN COMPLEXED WITH A PHOSPHINIC INHIBITOR'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Stromelysin-3 (ST3) is a matrix metalloproteinase (MMP-11) whose | + | Stromelysin-3 (ST3) is a matrix metalloproteinase (MMP-11) whose proteolytic activity plays an important role in tumorigenicity enhancement. In breast cancer, ST3 is a bad prognosis marker: its expression is associated with a poor clinical outcome. This enzyme therefore represents an attractive therapeutic target.The topology of matrix metalloproteinases (MMPs) is remarkably well conserved, making the design of highly specific inhibitors difficult. The major difference between MMPs lies in the S(1)' subsite, a well-defined hydrophobic pocket of variable depth. The present crystal structure, the first 3D-structure of the ST3 catalytic domain in interaction with a phosphinic inhibitor mimicking a (d, l) peptide, clearly demonstrates that its S(1)' pocket corresponds to a tunnel running through the enzyme. This open channel is filled by the inhibitor P(1)' group which adopts a constrained conformation to fit this pocket, together with two water molecules interacting with the ST3-specific residue Gln215. These observations provide clues for the design of more specific inhibitors and show how ST3 can accommodate a phosphinic inhibitor mimicking a (d, l) peptide.The presence of a water molecule interacting with one oxygen atom of the inhibitor phosphinyl group and the proline residue of the Met-turn suggests how the intermediate formed during proteolysis may be stabilized. Furthermore, the hydrogen bond distance observed between the methyl of the phosphinic group and the carbonyl group of Ala182 mimics the interaction between this carbonyl group and the amide group of the cleaved peptidic bond. Our crystal structure provides a good model to study the MMPs mechanism of proteolysis. |
==About this Structure== | ==About this Structure== | ||
| - | 1HV5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with ZN, CA, CPS and RXP as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1HV5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=CPS:'>CPS</scene> and <scene name='pdbligand=RXP:'>RXP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HV5 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Cuniasse, P.]] | [[Category: Cuniasse, P.]] | ||
[[Category: Dive, V.]] | [[Category: Dive, V.]] | ||
| - | [[Category: Gall, A | + | [[Category: Gall, A L.]] |
[[Category: Kannan, R.]] | [[Category: Kannan, R.]] | ||
[[Category: Moras, D.]] | [[Category: Moras, D.]] | ||
| - | [[Category: Rio, M | + | [[Category: Rio, M C.]] |
[[Category: Ruff, M.]] | [[Category: Ruff, M.]] | ||
[[Category: Yiotakis, A.]] | [[Category: Yiotakis, A.]] | ||
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[[Category: stromelysin-3]] | [[Category: stromelysin-3]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:05:10 2008'' |
Revision as of 11:05, 21 February 2008
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CRYSTAL STRUCTURE OF THE STROMELYSIN-3 (MMP-11) CATALYTIC DOMAIN COMPLEXED WITH A PHOSPHINIC INHIBITOR
Overview
Stromelysin-3 (ST3) is a matrix metalloproteinase (MMP-11) whose proteolytic activity plays an important role in tumorigenicity enhancement. In breast cancer, ST3 is a bad prognosis marker: its expression is associated with a poor clinical outcome. This enzyme therefore represents an attractive therapeutic target.The topology of matrix metalloproteinases (MMPs) is remarkably well conserved, making the design of highly specific inhibitors difficult. The major difference between MMPs lies in the S(1)' subsite, a well-defined hydrophobic pocket of variable depth. The present crystal structure, the first 3D-structure of the ST3 catalytic domain in interaction with a phosphinic inhibitor mimicking a (d, l) peptide, clearly demonstrates that its S(1)' pocket corresponds to a tunnel running through the enzyme. This open channel is filled by the inhibitor P(1)' group which adopts a constrained conformation to fit this pocket, together with two water molecules interacting with the ST3-specific residue Gln215. These observations provide clues for the design of more specific inhibitors and show how ST3 can accommodate a phosphinic inhibitor mimicking a (d, l) peptide.The presence of a water molecule interacting with one oxygen atom of the inhibitor phosphinyl group and the proline residue of the Met-turn suggests how the intermediate formed during proteolysis may be stabilized. Furthermore, the hydrogen bond distance observed between the methyl of the phosphinic group and the carbonyl group of Ala182 mimics the interaction between this carbonyl group and the amide group of the cleaved peptidic bond. Our crystal structure provides a good model to study the MMPs mechanism of proteolysis.
About this Structure
1HV5 is a Single protein structure of sequence from Mus musculus with , , and as ligands. Full crystallographic information is available from OCA.
Reference
Crystal structure of the stromelysin-3 (MMP-11) catalytic domain complexed with a phosphinic inhibitor mimicking the transition-state., Gall AL, Ruff M, Kannan R, Cuniasse P, Yiotakis A, Dive V, Rio MC, Basset P, Moras D, J Mol Biol. 2001 Mar 23;307(2):577-86. PMID:11254383
Page seeded by OCA on Thu Feb 21 13:05:10 2008
Categories: Mus musculus | Single protein | Basset, P. | Cuniasse, P. | Dive, V. | Gall, A L. | Kannan, R. | Moras, D. | Rio, M C. | Ruff, M. | Yiotakis, A. | CA | CPS | RXP | ZN | Inhibition | Phosphinic inhibitor | Stromelysin-3
