1vcu
From Proteopedia
(New page: 200px<br /> <applet load="1vcu" size="450" color="white" frame="true" align="right" spinBox="true" caption="1vcu, resolution 2.85Å" /> '''Structure of the hu...) |
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| - | [[Image:1vcu.gif|left|200px]]<br /> | + | [[Image:1vcu.gif|left|200px]]<br /><applet load="1vcu" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1vcu, resolution 2.85Å" /> | caption="1vcu, resolution 2.85Å" /> | ||
'''Structure of the human cytosolic sialidase Neu2 in complex with the inhibitor DANA'''<br /> | '''Structure of the human cytosolic sialidase Neu2 in complex with the inhibitor DANA'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Gangliosides play key roles in cell differentiation, cell-cell | + | Gangliosides play key roles in cell differentiation, cell-cell interactions, and transmembrane signaling. Sialidases hydrolyze sialic acids to produce asialo compounds, which is the first step of degradation processes of glycoproteins and gangliosides. Sialidase involvement has been implicated in some lysosomal storage disorders such as sialidosis and galactosialidosis. Neu2 is a recently identified human cytosolic sialidase. Here we report the first high resolution x-ray structures of mammalian sialidase, human Neu2, in its apo form and in complex with an inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA). The structure shows the canonical six-blade beta-propeller observed in viral and bacterial sialidases with its active site in a shallow crevice. In the complex structure, the inhibitor lies in the catalytic crevice surrounded by ten amino acids. In particular, the arginine triad, conserved among sialidases, aids in the proper positioning of the carboxylate group of DANA within the active site region. The tyrosine residue, Tyr(334), conserved among mammalian and bacterial sialidases as well as in viral neuraminidases, facilitates the enzymatic reaction by stabilizing a putative carbonium ion in the transition state. The loops containing Glu(111) and the catalytic aspartate Asp(46) are disordered in the apo form but upon binding of DANA become ordered to adopt two short alpha-helices to cover the inhibitor, illustrating the dynamic nature of substrate recognition. The N-acetyl and glycerol moieties of DANA are recognized by Neu2 residues not shared by bacterial sialidases and viral neuraminidases, which can be regarded as a key structural difference for potential drug design against bacteria, influenza, and other viruses. |
==About this Structure== | ==About this Structure== | ||
| - | 1VCU 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 DAN and EPE as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Exo-alpha-sialidase Exo-alpha-sialidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.18 3.2.1.18] Full crystallographic information is available from [http:// | + | 1VCU 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=DAN:'>DAN</scene> and <scene name='pdbligand=EPE:'>EPE</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Exo-alpha-sialidase Exo-alpha-sialidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.18 3.2.1.18] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1VCU OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Chavas, L | + | [[Category: Chavas, L M.G.]] |
[[Category: Fusi, P.]] | [[Category: Fusi, P.]] | ||
[[Category: Kato, R.]] | [[Category: Kato, R.]] | ||
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[[Category: sialidase]] | [[Category: sialidase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:33:53 2008'' |
Revision as of 13:33, 21 February 2008
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Structure of the human cytosolic sialidase Neu2 in complex with the inhibitor DANA
Overview
Gangliosides play key roles in cell differentiation, cell-cell interactions, and transmembrane signaling. Sialidases hydrolyze sialic acids to produce asialo compounds, which is the first step of degradation processes of glycoproteins and gangliosides. Sialidase involvement has been implicated in some lysosomal storage disorders such as sialidosis and galactosialidosis. Neu2 is a recently identified human cytosolic sialidase. Here we report the first high resolution x-ray structures of mammalian sialidase, human Neu2, in its apo form and in complex with an inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA). The structure shows the canonical six-blade beta-propeller observed in viral and bacterial sialidases with its active site in a shallow crevice. In the complex structure, the inhibitor lies in the catalytic crevice surrounded by ten amino acids. In particular, the arginine triad, conserved among sialidases, aids in the proper positioning of the carboxylate group of DANA within the active site region. The tyrosine residue, Tyr(334), conserved among mammalian and bacterial sialidases as well as in viral neuraminidases, facilitates the enzymatic reaction by stabilizing a putative carbonium ion in the transition state. The loops containing Glu(111) and the catalytic aspartate Asp(46) are disordered in the apo form but upon binding of DANA become ordered to adopt two short alpha-helices to cover the inhibitor, illustrating the dynamic nature of substrate recognition. The N-acetyl and glycerol moieties of DANA are recognized by Neu2 residues not shared by bacterial sialidases and viral neuraminidases, which can be regarded as a key structural difference for potential drug design against bacteria, influenza, and other viruses.
About this Structure
1VCU is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Exo-alpha-sialidase, with EC number 3.2.1.18 Full crystallographic information is available from OCA.
Reference
Crystal structure of the human cytosolic sialidase Neu2. Evidence for the dynamic nature of substrate recognition., Chavas LM, Tringali C, Fusi P, Venerando B, Tettamanti G, Kato R, Monti E, Wakatsuki S, J Biol Chem. 2005 Jan 7;280(1):469-75. Epub 2004 Oct 22. PMID:15501818
Page seeded by OCA on Thu Feb 21 15:33:53 2008
Categories: Exo-alpha-sialidase | Homo sapiens | Single protein | Chavas, L M.G. | Fusi, P. | Kato, R. | Monti, E. | Tettamanti, G. | Tringali, C. | Venerando, B. | Wakatsuki, S. | DAN | EPE | Dana | Ganglioside | Neuraminidase | Sialic acid | Sialidase
