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	<scene name='60/604481/Gtg/3'>A cap analog</scene> binds to the enzyme in a pocket near the AdoHcy.		<scene name='60/604481/Gtg/3'>A cap analog</scene> binds to the enzyme in a pocket near the AdoHcy.
	<scene name='60/604481/Interaction_gtg/1'>6 amino acids</scene> (Tyr 145, Leu216, Leu217, Asp218, Ser219, Tyr284) are involded in the binding of the cap analog.		<scene name='60/604481/Interaction_gtg/1'>6 amino acids</scene> (Tyr 145, Leu216, Leu217, Asp218, Ser219, Tyr284) are involded in the binding of the cap analog.
-	The cap makes Van der Walls contacts, hydrogen bond and water mediated bond.	+	The cap makes Van der Walls contacts thanks to side chain from Leu216, Leu217, Asp218, Ser219, Tyr284 makes a hydrogen bond and Tyr145 a water mediated bond.
	<ref name="Fabrega C, Hausmann S, Shen V, Shuman S, Lima CD. Structure and mechanism of mRNA cap (guanine-N7) methyltransferase. Mol Cell. 2004 Jan 16;13(1):77-89. ">PMID:14731396</ref>		<ref name="Fabrega C, Hausmann S, Shen V, Shuman S, Lima CD. Structure and mechanism of mRNA cap (guanine-N7) methyltransferase. Mol Cell. 2004 Jan 16;13(1):77-89. ">PMID:14731396</ref>
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	AdoHcys is in a pocket formed by amino acids of segment 2.		AdoHcys is in a pocket formed by amino acids of segment 2.
	<scene name='60/604481/Interaction_sah/1'>10 amino acids</scene> (Lys54, Gly72, Asp78, Asp94, Ile95, Asp122, Ser124, Gln140, Phe141, Ser142) are involved in the stabilisation of AdoHcys.		<scene name='60/604481/Interaction_sah/1'>10 amino acids</scene> (Lys54, Gly72, Asp78, Asp94, Ile95, Asp122, Ser124, Gln140, Phe141, Ser142) are involved in the stabilisation of AdoHcys.
-	The interactions between AdoHcys and the enzyme are made of : hydrogen bonds, Van der Walls interactions,electrostatic interaction and water mediated contact.	+	The interactions between AdoHcys and the enzyme are made of : {{clear}}
		+	hydrogen bonds are made by Asp122, Asp 94, Gln140, Gly72, Lys54 {{clear}}
		+	Van der Walls interactions are made by Ser142, Tyr124 and Ile95 {{clear}}
		+	an electrostatic interaction is made by Gln140, Phe141{{clear}}
		+	a water mediated contact is made by Asp78.
	<ref name="Fabrega C, Hausmann S, Shen V, Shuman S, Lima CD. Structure and mechanism of mRNA cap (guanine-N7) methyltransferase. Mol Cell. 2004 Jan 16;13(1):77-89. ">PMID:14731396</ref>		<ref name="Fabrega C, Hausmann S, Shen V, Shuman S, Lima CD. Structure and mechanism of mRNA cap (guanine-N7) methyltransferase. Mol Cell. 2004 Jan 16;13(1):77-89. ">PMID:14731396</ref>

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Revision as of 10:14, 2 January 2015

This Sandbox is Reserved from 15/11/2014, through 15/05/2015 for use in the course "Biomolecule" taught by Bruno Kieffer at the Strasbourg University. This reservation includes Sandbox Reserved 951 through Sandbox Reserved 975.

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mRNA Cap (Guanine-N7) Methyltransferase (Ecm1)

spinqualitylabelsall models Ecm1 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Contents 1 Biological role 2 Structure 3 Interaction 3.1 Cap Analog Binding (7-Methylguanosine-5-Triphosphate-5-Guanosine) 3.2 AdoHcy Binding (S-Adenosyl-L-Homocysteine) 4 Mechanism 5 References

Biological role

Structure

Interaction

Cap Analog Binding (7-Methylguanosine-5-Triphosphate-5-Guanosine)

Image:M7GpppG.png

binds to the enzyme in a pocket near the AdoHcy. (Tyr 145, Leu216, Leu217, Asp218, Ser219, Tyr284) are involded in the binding of the cap analog. The cap makes Van der Walls contacts thanks to side chain from Leu216, Leu217, Asp218, Ser219, Tyr284 makes a hydrogen bond and Tyr145 a water mediated bond. ^[1]

Image:Image methyl acceptor specificity.png

As we can see on the figure^[2] , the enzyme specifically binds to guanine. This specificity is achieved through the recognition by the enzyme residues through hydrogen bonds of the guanine N1, N3, and O6 atoms. We remark also that the methyltransferase is not able to discrminate between ribose and deoxyribose nucleoside sugars.

AdoHcy Binding (S-Adenosyl-L-Homocysteine)

The mRNA Cap Methyltransferase bind to which is the product of the methyl donor AdoMet after the methylation. AdoHcys is in a pocket formed by amino acids of segment 2. (Lys54, Gly72, Asp78, Asp94, Ile95, Asp122, Ser124, Gln140, Phe141, Ser142) are involved in the stabilisation of AdoHcys.

The interactions between AdoHcys and the enzyme are made of : hydrogen bonds are made by Asp122, Asp 94, Gln140, Gly72, Lys54 Van der Walls interactions are made by Ser142, Tyr124 and Ile95 an electrostatic interaction is made by Gln140, Phe141

a water mediated contact is made by Asp78.

^[1]

Mechanism

This enzyme catalyse N-methyl transfer from AdoMet (S-adenosylmethionine) to GpppRNA, this reaction produce 7-methyl-GpppRNA and AdoHcy. This reaction is made trough a SN2 mechanism. We remark that there is no contact between the enzyme and the guanine N-7 nucleophile, the AdoMet methyl carbon, or the AdoHcy sulfur leaving group. Indeed the enzyme does not stabilize the transition state of the chemical reaction, does not promote the activation of the nucleophile or the explusion of the leaving group. mRNA Cap Methyltransferase brings the two substrates closer and orientates the substrates to facilitate the methyl transfer.

References

1. ↑ ^{1.0 1.1} Fabrega C, Hausmann S, Shen V, Shuman S, Lima CD. Structure and mechanism of mRNA cap (guanine-N7) methyltransferase. Mol Cell. 2004 Jan 16;13(1):77-89. PMID:14731396
2. ↑ Hausmann S, Zheng S, Fabrega C, Schneller SW, Lima CD, Shuman S. Encephalitozoon cuniculi mRNA cap (guanine N-7) methyltransferase: methyl acceptor specificity, inhibition BY S-adenosylmethionine analogs, and structure-guided mutational analysis. J Biol Chem. 2005 May 27;280(21):20404-12. Epub 2005 Mar 9. PMID:15760890 doi:10.1074/jbc.M501073200