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[[Image:1hl9.gif|left|200px]]<br />
<applet load="1hl9" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1hl9, resolution 2.25&Aring;" />
'''CRYSTAL STRUCTURE OF THERMOTOGA MARITIMA ALPHA-FUCOSIDASE IN COMPLEX WITH A MECHANISM BASED INHIBITOR'''<br />


==Overview==
==CRYSTAL STRUCTURE OF THERMOTOGA MARITIMA ALPHA-FUCOSIDASE IN COMPLEX WITH A MECHANISM BASED INHIBITOR==
Fucosylated glycoconjugates are involved in numerous biological events, and alpha-l-fucosidases, the enzymes responsible for their processing, are, therefore of crucial importance. Deficiency in alpha-l-fucosidase activity, is associated with fucosidosis, a lysosomal storage disorder characterized, by rapid neurodegeneration, resulting in severe mental and motor, deterioration. To gain insight into alpha-l-fucosidase function at the, molecular level, we have determined the crystal structure of Thermotoga, maritima alpha-l-fucosidase. This enzyme assembles as a hexamer and, displays a two-domain fold, composed of a catalytic (beta/alpha)(8)-like, domain and a C-terminal beta-sandwich domain. The structures of an, enzyme-product complex and of a covalent glycosyl-enzyme intermediate, coupled with kinetic and mutagenesis studies, allowed us to identify the, catalytic nucleophile, Asp(244), and the Bronsted acid/base, Glu(266)., Because T. maritima alpha-l-fucosidase occupies a unique evolutionary, position, being far more closely related to the mammalian enzymes than to, any other prokaryotic homolog, a structural model of the human enzyme was, built to document the structural consequences of the genetic mutations, associated with fucosidosis.
<StructureSection load='1hl9' size='340' side='right'caption='[[1hl9]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1hl9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Thermotoga_maritima_MSB8 Thermotoga maritima MSB8]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HL9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1HL9 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FUF:2-DEOXY-2-FLUORO-BETA-L-FUCOPYRANOSE'>FUF</scene>, <scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1hl9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hl9 OCA], [https://pdbe.org/1hl9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1hl9 RCSB], [https://www.ebi.ac.uk/pdbsum/1hl9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1hl9 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q9WYE2_THEMA Q9WYE2_THEMA]
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hl/1hl9_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1hl9 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Fucosylated glycoconjugates are involved in numerous biological events, and alpha-l-fucosidases, the enzymes responsible for their processing, are therefore of crucial importance. Deficiency in alpha-l-fucosidase activity is associated with fucosidosis, a lysosomal storage disorder characterized by rapid neurodegeneration, resulting in severe mental and motor deterioration. To gain insight into alpha-l-fucosidase function at the molecular level, we have determined the crystal structure of Thermotoga maritima alpha-l-fucosidase. This enzyme assembles as a hexamer and displays a two-domain fold, composed of a catalytic (beta/alpha)(8)-like domain and a C-terminal beta-sandwich domain. The structures of an enzyme-product complex and of a covalent glycosyl-enzyme intermediate, coupled with kinetic and mutagenesis studies, allowed us to identify the catalytic nucleophile, Asp(244), and the Bronsted acid/base, Glu(266). Because T. maritima alpha-l-fucosidase occupies a unique evolutionary position, being far more closely related to the mammalian enzymes than to any other prokaryotic homolog, a structural model of the human enzyme was built to document the structural consequences of the genetic mutations associated with fucosidosis.


==About this Structure==
Crystal structure of Thermotoga maritima alpha-L-fucosidase. Insights into the catalytic mechanism and the molecular basis for fucosidosis.,Sulzenbacher G, Bignon C, Nishimura T, Tarling CA, Withers SG, Henrissat B, Bourne Y J Biol Chem. 2004 Mar 26;279(13):13119-28. Epub 2004 Jan 8. PMID:14715651<ref>PMID:14715651</ref>
1HL9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Thermotoga_maritima Thermotoga maritima] with FUF as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Alpha-L-fucosidase Alpha-L-fucosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.51 3.2.1.51] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1HL9 OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
Crystal structure of Thermotoga maritima alpha-L-fucosidase. Insights into the catalytic mechanism and the molecular basis for fucosidosis., Sulzenbacher G, Bignon C, Nishimura T, Tarling CA, Withers SG, Henrissat B, Bourne Y, J Biol Chem. 2004 Mar 26;279(13):13119-28. Epub 2004 Jan 8. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=14715651 14715651]
</div>
[[Category: Alpha-L-fucosidase]]
<div class="pdbe-citations 1hl9" style="background-color:#fffaf0;"></div>
[[Category: Single protein]]
== References ==
[[Category: Thermotoga maritima]]
<references/>
[[Category: Bignon, C.]]
__TOC__
[[Category: Bourne, Y.]]
</StructureSection>
[[Category: Henrissat, B.]]
[[Category: Large Structures]]
[[Category: Sulzenbacher, G.]]
[[Category: Thermotoga maritima MSB8]]
[[Category: FUF]]
[[Category: Bignon C]]
[[Category: alpha-l-fucosidase]]
[[Category: Bourne Y]]
[[Category: glycoside hydrolase]]
[[Category: Henrissat B]]
[[Category: glycosyl-enzyme intermediate]]
[[Category: Sulzenbacher G]]
[[Category: thermostable]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov  5 15:31:28 2007''

Latest revision as of 12:28, 13 December 2023

CRYSTAL STRUCTURE OF THERMOTOGA MARITIMA ALPHA-FUCOSIDASE IN COMPLEX WITH A MECHANISM BASED INHIBITOR

1hl9, resolution 2.25Å

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