Matrix Metalloproteinase 12 - Revision history

Michal Harel at 08:13, 18 July 2011

Michal Harel — Mon, 18 Jul 2011 08:13:19 GMT

←Older revision		Revision as of 08:13, 18 July 2011
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-		+
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-	~~{{STRUCTURE_2oxu\|~~ ~~PDB=2oxu \| SCENE=Matrix_Metalloproteinase_12/Structintro/1 }}~~	+

	{{STRUCTURE_2oxu\| PDB=2oxu \| SIZE=300\| SCENE=Matrix_Metalloproteinase_12/Structintro/1\|right\| CAPTION= Human MMP12 complex with Ca+2 and Zn+2 ions, [[2oxu]] }}		{{STRUCTURE_2oxu\| PDB=2oxu \| SIZE=300\| SCENE=Matrix_Metalloproteinase_12/Structintro/1\|right\| CAPTION= Human MMP12 complex with Ca+2 and Zn+2 ions, [[2oxu]] }}

Michal Harel at 08:12, 18 July 2011

Michal Harel — Mon, 18 Jul 2011 08:12:48 GMT

←Older revision		Revision as of 08:12, 18 July 2011
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	{{STRUCTURE_2oxu\| PDB=2oxu \| SCENE=Matrix_Metalloproteinase_12/Structintro/1 }}		{{STRUCTURE_2oxu\| PDB=2oxu \| SCENE=Matrix_Metalloproteinase_12/Structintro/1 }}

		+	{{STRUCTURE_2oxu\| PDB=2oxu \| SIZE=300\| SCENE=Matrix_Metalloproteinase_12/Structintro/1\|right\| CAPTION= Human MMP12 complex with Ca+2 and Zn+2 ions, [[2oxu]] }}

	[[Matrix Metalloproteinase 12]] is a human protease which is involved in tissue remodelling and cell signalling. The MMPs are secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases.		[[Matrix Metalloproteinase 12]] is a human protease which is involved in tissue remodelling and cell signalling. The MMPs are secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases.

Michal Harel at 08:08, 18 July 2011

Michal Harel — Mon, 18 Jul 2011 08:08:45 GMT

←Older revision		Revision as of 08:08, 18 July 2011
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	Furthermore, researchers have successfully produced synthetic inhibitors : These inhibitors contain a chelating group, which binds the catalytic zinc atom involved in the catalytic site. Common chelating groups include hydroxamates, carboxylates, thiols, and phosphinyls. Hydroxymates are particularly potent inhibitors of MMPs thanks to their bidentate chelation of the zinc atom. A 2oxu inhibitor can also inhibit other MMPs after a few modifications : Only the substituents interacting with the pocket have to be modified because of the various binding pockets of the MMPs.		Furthermore, researchers have successfully produced synthetic inhibitors : These inhibitors contain a chelating group, which binds the catalytic zinc atom involved in the catalytic site. Common chelating groups include hydroxamates, carboxylates, thiols, and phosphinyls. Hydroxymates are particularly potent inhibitors of MMPs thanks to their bidentate chelation of the zinc atom. A 2oxu inhibitor can also inhibit other MMPs after a few modifications : Only the substituents interacting with the pocket have to be modified because of the various binding pockets of the MMPs.
	That means that from a a single inhibitor, researchers are able to create more or less specificity toward several enzymes.		That means that from a a single inhibitor, researchers are able to create more or less specificity toward several enzymes.
		+
		+	==3D structures of matrix metalloproteinase ==
		+
		+	[[Matrix metalloproteinase]]

	== References ==		== References ==

Claire Dupont at 18:24, 30 November 2010

Claire Dupont — Tue, 30 Nov 2010 18:24:50 GMT

←Older revision		Revision as of 18:24, 30 November 2010
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-	A proton of one of the three H2O moves to the <scene name='~~User:Julie_Frentzel~~/~~Sandbox_1~~/~~L/1~~'>Glu 219</scene> catalytic site's residue.	+	A proton of one of the three H2O moves to the <scene name='Matrix_Metalloproteinase_12/Zn/3'>Glu 219</scene> catalytic site's residue.
	It creates a hydroxyl group with a high nucleophilic character.		It creates a hydroxyl group with a high nucleophilic character.
	That leads to a nucleophilic attack by zinc-coordinated hydroxyl group, on one of the carbonyl group of the substrate (Gly206).		That leads to a nucleophilic attack by zinc-coordinated hydroxyl group, on one of the carbonyl group of the substrate (Gly206).

Julie Frentzel at 10:34, 26 November 2010

Julie Frentzel — Fri, 26 Nov 2010 10:34:43 GMT

←Older revision		Revision as of 10:34, 26 November 2010
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	=== Substrate's fixation ===		=== Substrate's fixation ===

-	The <scene name='~~User:Julie_Frentzel/Sandbox_1~~/Active_site/1'>active site of the enzyme</scene> is composed by one Glu residue near 3 His residues which maintain a <scene name='User:Julie_Frentzel/Sandbox_1/Zinc_et_eau/1'>Zn2+ atom coordinated with three water molecules</scene>. One of them is as well bound to the Glu residue thanks to a hydrogen bond. The second Zn2+ atom is not involved in the active site. At first, the Gly 206 residue of the substrate binds the active site thanks to the Zn2+ atom. When it binds it takes the place of unstable water molecules and establishes stabilizing interactions with the active site thanks to its C terminal part. Then, the <scene name='User:Julie_Frentzel/Sandbox_1/J/1'>Ala 182</scene> residue of the enzyme makes a hydrogen bond with the NH group of the substrate: this allows the substrate to enter the cavity of the catalytic site.	+	The <scene name='Matrix_Metalloproteinase_12/Active_site/1'>active site of the enzyme</scene> is composed by one Glu residue near 3 His residues which maintain a <scene name='User:Julie_Frentzel/Sandbox_1/Zinc_et_eau/1'>Zn2+ atom coordinated with three water molecules</scene>. One of them is as well bound to the Glu residue thanks to a hydrogen bond. The second Zn2+ atom is not involved in the active site. At first, the Gly 206 residue of the substrate binds the active site thanks to the Zn2+ atom. When it binds it takes the place of unstable water molecules and establishes stabilizing interactions with the active site thanks to its C terminal part. Then, the <scene name='User:Julie_Frentzel/Sandbox_1/J/1'>Ala 182</scene> residue of the enzyme makes a hydrogen bond with the NH group of the substrate: this allows the substrate to enter the cavity of the catalytic site.
	The rest of the protein is stabilized by 4 hydrogen bonds with the amino acid located in the cavity.		The rest of the protein is stabilized by 4 hydrogen bonds with the amino acid located in the cavity.

Julie Frentzel at 10:31, 26 November 2010

Julie Frentzel — Fri, 26 Nov 2010 10:31:28 GMT

←Older revision		Revision as of 10:31, 26 November 2010
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	Thanks to X-ray crystallography, the structure of 2oxu has been solved with 1,24 Å resolution.		Thanks to X-ray crystallography, the structure of 2oxu has been solved with 1,24 Å resolution.
-	This enzyme consists of <scene name='Matrix_Metalloproteinase_12/Helixes/1'>four alpha helixes</scene> and <scene name='~~User:Julie_Frentzel/Sandbox_1~~/Sheets/1'>five beta sheets</scene> organized like as you can see on the J-mol figure.	+	This enzyme consists of <scene name='Matrix_Metalloproteinase_12/Helixes/1'>four alpha helixes</scene> and <scene name='Matrix_Metalloproteinase_12/Sheets/1'>five beta sheets</scene> organized like as you can see on the J-mol figure.

	The hydrolysis of the Substrate can be divided in four essential events:		The hydrolysis of the Substrate can be divided in four essential events:

Julie Frentzel at 10:24, 26 November 2010

Julie Frentzel — Fri, 26 Nov 2010 10:24:46 GMT

←Older revision		Revision as of 10:24, 26 November 2010
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	Thanks to X-ray crystallography, the structure of 2oxu has been solved with 1,24 Å resolution.		Thanks to X-ray crystallography, the structure of 2oxu has been solved with 1,24 Å resolution.
-	This enzyme consists of <scene name='~~User:Julie_Frentzel/Sandbox_1~~/Helixes/1'>four alpha helixes</scene> and <scene name='User:Julie_Frentzel/Sandbox_1/Sheets/1'>five beta sheets</scene> organized like as you can see on the J-mol figure.	+	This enzyme consists of <scene name='Matrix_Metalloproteinase_12/Helixes/1'>four alpha helixes</scene> and <scene name='User:Julie_Frentzel/Sandbox_1/Sheets/1'>five beta sheets</scene> organized like as you can see on the J-mol figure.

	The hydrolysis of the Substrate can be divided in four essential events:		The hydrolysis of the Substrate can be divided in four essential events:

Julie Frentzel at 10:21, 26 November 2010

Julie Frentzel — Fri, 26 Nov 2010 10:21:24 GMT

←Older revision		Revision as of 10:21, 26 November 2010
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	[[Matrix Metalloproteinase 12]] is a human protease which is involved in tissue remodelling and cell signalling. The MMPs are secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases.		[[Matrix Metalloproteinase 12]] is a human protease which is involved in tissue remodelling and cell signalling. The MMPs are secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases.
	MMPs are sorted into 17 classes depending on their localization in the cell, and on their substrates. For instance, MMP12 is a macrophage metalloelastane coded by the MMP12 gene.		MMPs are sorted into 17 classes depending on their localization in the cell, and on their substrates. For instance, MMP12 is a macrophage metalloelastane coded by the MMP12 gene.
-	In healthy cells, 2oxu is implied in tissue remodelling and cell signalling. Its role is to allow the migration of the macrophages in tissues by hydrolysing soluble and insoluble elastin of the extracellular matrix by involving two cofactors: <scene name='Matrix_Metalloproteinase_12/Zn/1'>zinc</scene> and <scene	+	In healthy cells, 2oxu is implied in tissue remodelling and cell signalling. Its role is to allow the migration of the macrophages in tissues by hydrolysing soluble and insoluble elastin of the extracellular matrix by involving two cofactors: <scene name='Matrix_Metalloproteinase_12/Zn/2'>zinc</scene> and <scene
	name='Matrix_Metalloproteinase_12/Ca/1'>calcium</scene>. Zn2+ atoms are part of the enzyme whereas Ca2+ atoms are hydrogen bounded to the backbone of the protein.		name='Matrix_Metalloproteinase_12/Ca/1'>calcium</scene>. Zn2+ atoms are part of the enzyme whereas Ca2+ atoms are hydrogen bounded to the backbone of the protein.
	Because of its activity, this protein is also involved in metastasis and tumor development; that's why it is considered as an important target for drug therapies.		Because of its activity, this protein is also involved in metastasis and tumor development; that's why it is considered as an important target for drug therapies.

Julie Frentzel at 10:11, 26 November 2010

Julie Frentzel — Fri, 26 Nov 2010 10:11:14 GMT

←Older revision		Revision as of 10:11, 26 November 2010
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	MMPs are sorted into 17 classes depending on their localization in the cell, and on their substrates. For instance, MMP12 is a macrophage metalloelastane coded by the MMP12 gene.		MMPs are sorted into 17 classes depending on their localization in the cell, and on their substrates. For instance, MMP12 is a macrophage metalloelastane coded by the MMP12 gene.
	In healthy cells, 2oxu is implied in tissue remodelling and cell signalling. Its role is to allow the migration of the macrophages in tissues by hydrolysing soluble and insoluble elastin of the extracellular matrix by involving two cofactors: <scene name='Matrix_Metalloproteinase_12/Zn/1'>zinc</scene> and <scene		In healthy cells, 2oxu is implied in tissue remodelling and cell signalling. Its role is to allow the migration of the macrophages in tissues by hydrolysing soluble and insoluble elastin of the extracellular matrix by involving two cofactors: <scene name='Matrix_Metalloproteinase_12/Zn/1'>zinc</scene> and <scene
-	name='~~User:Julie_Frentzel/Sandbox_1~~/Ca/1'>calcium</scene>. Zn2+ atoms are part of the enzyme whereas Ca2+ atoms are hydrogen bounded to the backbone of the protein.	+	name='Matrix_Metalloproteinase_12/Ca/1'>calcium</scene>. Zn2+ atoms are part of the enzyme whereas Ca2+ atoms are hydrogen bounded to the backbone of the protein.
	Because of its activity, this protein is also involved in metastasis and tumor development; that's why it is considered as an important target for drug therapies.		Because of its activity, this protein is also involved in metastasis and tumor development; that's why it is considered as an important target for drug therapies.

Julie Frentzel at 10:06, 26 November 2010

Julie Frentzel — Fri, 26 Nov 2010 10:06:14 GMT

←Older revision		Revision as of 10:06, 26 November 2010
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	[[Matrix Metalloproteinase 12]] is a human protease which is involved in tissue remodelling and cell signalling. The MMPs are secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases.		[[Matrix Metalloproteinase 12]] is a human protease which is involved in tissue remodelling and cell signalling. The MMPs are secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases.
	MMPs are sorted into 17 classes depending on their localization in the cell, and on their substrates. For instance, MMP12 is a macrophage metalloelastane coded by the MMP12 gene.		MMPs are sorted into 17 classes depending on their localization in the cell, and on their substrates. For instance, MMP12 is a macrophage metalloelastane coded by the MMP12 gene.
-	In healthy cells, 2oxu is implied in tissue remodelling and cell signalling. Its role is to allow the migration of the macrophages in tissues by hydrolysing soluble and insoluble elastin of the extracellular matrix by involving two cofactors: <scene name='~~User:Julie_Frentzel/Sandbox_1~~/Zn/1'>zinc</scene> and <scene	+	In healthy cells, 2oxu is implied in tissue remodelling and cell signalling. Its role is to allow the migration of the macrophages in tissues by hydrolysing soluble and insoluble elastin of the extracellular matrix by involving two cofactors: <scene name='Matrix_Metalloproteinase_12/Zn/1'>zinc</scene> and <scene
	name='User:Julie_Frentzel/Sandbox_1/Ca/1'>calcium</scene>. Zn2+ atoms are part of the enzyme whereas Ca2+ atoms are hydrogen bounded to the backbone of the protein.		name='User:Julie_Frentzel/Sandbox_1/Ca/1'>calcium</scene>. Zn2+ atoms are part of the enzyme whereas Ca2+ atoms are hydrogen bounded to the backbone of the protein.
	Because of its activity, this protein is also involved in metastasis and tumor development; that's why it is considered as an important target for drug therapies.		Because of its activity, this protein is also involved in metastasis and tumor development; that's why it is considered as an important target for drug therapies.