1eye

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[[Image:1eye.gif|left|200px]]<br /><applet load="1eye" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1eye, resolution 1.7&Aring;" />
 
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'''1.7 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTEROATE SYNTHASE (DHPS) FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH 6-HYDROXYMETHYLPTERIN MONOPHOSPHATE'''<br />
 
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==Overview==
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==1.7 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTEROATE SYNTHASE (DHPS) FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH 6-HYDROXYMETHYLPTERIN MONOPHOSPHATE==
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The enzyme 7,8-dihydropteroate synthase (DHPS) catalyzes the condensation of para-aminobenzoic acid (pABA) with 6-hydroxymethyl-7, 8-dihydropterin-pyrophosphate to form 7,8-dihydropteroate and pyrophosphate. DHPS is essential for the de novo synthesis of folate in prokaryotes, lower eukaryotes, and in plants, but is absent in mammals. Inhibition of this enzyme's activity by sulfonamide and sulfone drugs depletes the folate pool, resulting in growth inhibition and cell death. Here, we report the 1.7 A resolution crystal structure of the binary complex of 6-hydroxymethylpterin monophosphate (PtP) with DHPS from Mycobacterium tuberculosis (Mtb), a pathogen responsible for the death of millions of human beings each year. Comparison to other DHPS structures reveals that the M. tuberculosis DHPS structure is in a unique conformation in which loop 1 closes over the active site. The Mtb DHPS structure hints at a mechanism in which both loops 1 and 2 play important roles in catalysis by shielding the active site from bulk solvent and allowing pyrophosphoryl transfer to occur. A binding mode for pABA, sulfonamides and sulfones is suggested based on: (i) the new conformation of the closed loop 1; (ii) the distribution of dapsone and sulfonamide resistance mutations; (iii) the observed direction of the bond between the 6-methyl carbon atom and the bridging oxygen atom to the alpha-phosphate group in the Mtb DHPS:PtP binary complex; and (iv) the conformation of loop 2 in the Escherichia coli DHPS structure. Finally, the Mtb DHPS structure reveals a highly conserved pterin binding pocket that may be exploited for the design of novel antimycobacterial agents.
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<StructureSection load='1eye' size='340' side='right'caption='[[1eye]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1eye]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EYE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EYE FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PMM:PTERIN-6-YL-METHYL-MONOPHOSPHATE'>PMM</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1eye FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1eye OCA], [https://pdbe.org/1eye PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1eye RCSB], [https://www.ebi.ac.uk/pdbsum/1eye PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1eye ProSAT], [https://www.topsan.org/Proteins/TBSGC/1eye TOPSAN]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/DHPS1_MYCTU DHPS1_MYCTU] Catalyzes the condensation of para-aminobenzoate (pABA) with 6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPt-PP) to form 7,8-dihydropteroate (H2Pte), the immediate precursor of folate derivatives.<ref>PMID:10542185</ref> <ref>PMID:23118010</ref> <ref>PMID:23779105</ref> Is involved in the bioactivation of the antituberculous drug para-aminosalicylic acid (PAS). PAS is a close structural analog of pABA and acts as an alternative substrate for DHPS, leading to hydroxy-dihydropteroate (H2PtePAS). Metabolomic studies show that PAS, despite its in vitro activity as a competitive inhibitor of DHPS, does not inhibit growth of M.tuberculosis by inhibiting DHPS. PAS exerts its antimycobacterial activity through its effects on M.tuberculosis folate metabolism downstream of DHPS. PAS poisons folate-dependent pathways not only by serving as a replacement substrate for DHPS but also by the products of that reaction serving as replacement substrates and/or inhibitors of subsequent enzymes.<ref>PMID:23118010</ref> <ref>PMID:23779105</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ey/1eye_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1eye ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1EYE is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=PMM:'>PMM</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydropteroate_synthase Dihydropteroate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.15 2.5.1.15] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EYE OCA].
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*[[Dihydropteroate synthase 3D structures|Dihydropteroate synthase 3D structures]]
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== References ==
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==Reference==
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<references/>
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Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action., Baca AM, Sirawaraporn R, Turley S, Sirawaraporn W, Hol WG, J Mol Biol. 2000 Oct 6;302(5):1193-212. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11007651 11007651]
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__TOC__
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[[Category: Dihydropteroate synthase]]
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</StructureSection>
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[[Category: Mycobacterium tuberculosis]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Mycobacterium tuberculosis H37Rv]]
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[[Category: Baca, A M.]]
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[[Category: Baca AM]]
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[[Category: Hol, W G.J.]]
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[[Category: Hol WGJ]]
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[[Category: Sirawaraporn, R.]]
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[[Category: Sirawaraporn R]]
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[[Category: Sirawaraporn, W.]]
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[[Category: Sirawaraporn W]]
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[[Category: Turley, S.]]
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[[Category: Turley S]]
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[[Category: MG]]
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[[Category: PMM]]
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[[Category: alpha-beta barrel]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:32:49 2008''
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Current revision

1.7 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTEROATE SYNTHASE (DHPS) FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH 6-HYDROXYMETHYLPTERIN MONOPHOSPHATE

PDB ID 1eye

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