6i6f: Difference between revisions
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New page: '''Unreleased structure''' The entry 6i6f is ON HOLD Authors: Alen, J., Schade, M., Wagener, M. Description: SEPIAPTERIN REDUCTASE IN COMPLEX WITH LIGAND GRTF1060-0 [[Category: Unrelea... |
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The | ==SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 1== | ||
<StructureSection load='6i6f' size='340' side='right'caption='[[6i6f]], [[Resolution|resolution]] 1.94Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6i6f]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I6F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I6F FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=H4E:ethyl+4-azanyl-3-bromanyl-benzoate'>H4E</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SPR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Sepiapterin_reductase_(L-erythro-7,8-dihydrobiopterin_forming) Sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.153 1.1.1.153] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6i6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i6f OCA], [http://pdbe.org/6i6f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6i6f RCSB], [http://www.ebi.ac.uk/pdbsum/6i6f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6i6f ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[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> | |||
== Function == | |||
[[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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Genome-wide-association studies in chronic low back pain patients identified sepiapterin reductase as a high interest target for developing new analgesics. Here we used (19)F NMR fragment screening for the discovery of novel, ligand-efficient SPR inhibitors. We report the crystal structures of six chemically diverse inhibitors complexed with SPR, identifying relevant interactions and binding modes in the sepiapterin pocket. Exploration of our initial fragment screening hit led to double-digit nanomolar inhibitors of SPR with excellent ligand efficiency. | |||
Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors.,Alen J, Schade M, Wagener M, Christian F, Nordhoff S, Merla B, Dunkern TR, Bahrenberg G, Ratcliffe P J Med Chem. 2019 Jun 25. doi: 10.1021/acs.jmedchem.9b00218. PMID:31244106<ref>PMID:31244106</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6i6f" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Alen, J]] | [[Category: Alen, J]] | ||
[[Category: Blaesse, M]] | |||
[[Category: Schade, M]] | [[Category: Schade, M]] | ||
[[Category: Wagener, M]] | |||
[[Category: Oxidoreductase]] | |||
[[Category: Proteros biostructures gmbh]] | |||
[[Category: Sepiapterin-reductase]] | |||
Latest revision as of 11:35, 24 July 2019
SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 1SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 1
Structural highlights
Disease[SPRE_HUMAN] Defects in SPR are the cause of dystonia DOPA-responsive due to sepiapterin reductase deficiency (DRDSPRD) [MIM: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.[1] [2] [3] Function[SPRE_HUMAN] Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin. Publication Abstract from PubMedGenome-wide-association studies in chronic low back pain patients identified sepiapterin reductase as a high interest target for developing new analgesics. Here we used (19)F NMR fragment screening for the discovery of novel, ligand-efficient SPR inhibitors. We report the crystal structures of six chemically diverse inhibitors complexed with SPR, identifying relevant interactions and binding modes in the sepiapterin pocket. Exploration of our initial fragment screening hit led to double-digit nanomolar inhibitors of SPR with excellent ligand efficiency. Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors.,Alen J, Schade M, Wagener M, Christian F, Nordhoff S, Merla B, Dunkern TR, Bahrenberg G, Ratcliffe P J Med Chem. 2019 Jun 25. doi: 10.1021/acs.jmedchem.9b00218. PMID:31244106[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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