4hwk

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{{STRUCTURE_4hwk| PDB=4hwk | SCENE= }}
 
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===Crystal structure of human sepiapterin reductase in complex with sulfapyridine===
 
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{{ABSTRACT_PUBMED_23704574}}
 
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==Disease==
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==Crystal structure of human sepiapterin reductase in complex with sulfapyridine==
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[[http://www.uniprot.org/uniprot/SPRE_HUMAN SPRE_HUMAN]] Defects in SPR are the cause of dystonia DOPA-responsive due to sepiapterin reductase deficiency (DRDSPRD) [MIM:[http://omim.org/entry/612716 612716]]. In the majority of cases, patients manifest progressive psychomotor retardation, dystonia and spasticity. Cognitive anomalies are also often present. The disease is due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in BH4 synthesis. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures.<ref>PMID:11443547</ref> <ref>PMID:16650784</ref> <ref>PMID:17159114</ref>
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<StructureSection load='4hwk' size='340' side='right'caption='[[4hwk]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4hwk]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HWK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HWK 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]] 2.4&#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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SFY:4-AMINO-N-(PYRIDIN-2-YL)BENZENESULFONAMIDE'>SFY</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4hwk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hwk OCA], [https://pdbe.org/4hwk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hwk RCSB], [https://www.ebi.ac.uk/pdbsum/4hwk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hwk ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/SPRE_HUMAN SPRE_HUMAN] Defects in SPR are the cause of dystonia DOPA-responsive due to sepiapterin reductase deficiency (DRDSPRD) [MIM:[https://omim.org/entry/612716 612716]. In the majority of cases, patients manifest progressive psychomotor retardation, dystonia and spasticity. Cognitive anomalies are also often present. The disease is due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in BH4 synthesis. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures.<ref>PMID:11443547</ref> <ref>PMID:16650784</ref> <ref>PMID:17159114</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/SPRE_HUMAN SPRE_HUMAN] Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The introduction of sulfa drugs for the chemotherapy of bacterial infections in 1935 revolutionized medicine. Although their mechanism of action is understood, the molecular bases for most of their side effects remain obscure. Here, we report that sulfamethoxazole and other sulfa drugs interfere with tetrahydrobiopterin biosynthesis through inhibition of sepiapterin reductase. Crystal structures of sepiapterin reductase with bound sulfa drugs reveal how structurally diverse sulfa drugs achieve specific inhibition of the enzyme. The effect of sulfa drugs on tetrahydrobiopterin-dependent neurotransmitter biosynthesis in cell-based assays provides a rationale for some of their central nervous system-related side effects, particularly in high-dose sulfamethoxazole therapy of Pneumocystis pneumonia. Our findings reveal an unexpected aspect of the pharmacology of sulfa drugs and might translate into their improved medical use.
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==Function==
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Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs.,Haruki H, Pedersen MG, Gorska KI, Pojer F, Johnsson K Science. 2013 May 24;340(6135):987-91. doi: 10.1126/science.1232972. PMID:23704574<ref>PMID:23704574</ref>
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[[http://www.uniprot.org/uniprot/SPRE_HUMAN SPRE_HUMAN]] Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4hwk]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HWK OCA].
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</div>
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<div class="pdbe-citations 4hwk" style="background-color:#fffaf0;"></div>
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==Reference==
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== References ==
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<ref group="xtra">PMID:023704574</ref><references group="xtra"/><references/>
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Johnsson, K.]]
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[[Category: Large Structures]]
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[[Category: Pedersen, M Groenlund.]]
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[[Category: Groenlund Pedersen M]]
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[[Category: Pojer, F.]]
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[[Category: Johnsson K]]
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[[Category: Oxidoreductase-antibiotic complex]]
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[[Category: Pojer F]]
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[[Category: Reductase]]
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Current revision

Crystal structure of human sepiapterin reductase in complex with sulfapyridine

PDB ID 4hwk

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