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6i6p

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SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 3

Structural highlights

6i6p is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	SPR (HUMAN)
Activity:	Sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming), with EC number 1.1.1.153
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bonafe L, Thony B, Penzien JM, Czarnecki B, Blau N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am J Hum Genet. 2001 Aug;69(2):269-77. Epub 2001 Jul 6. PMID:11443547 doi:10.1086/321970
↑ Abeling NG, Duran M, Bakker HD, Stroomer L, Thony B, Blau N, Booij J, Poll-The BT. Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia. Mol Genet Metab. 2006 Sep-Oct;89(1-2):116-20. Epub 2006 May 2. PMID:16650784 doi:10.1016/j.ymgme.2006.03.010
↑ Friedman J, Hyland K, Blau N, MacCollin M. Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology. 2006 Dec 12;67(11):2032-5. PMID:17159114 doi:10.1212/01.wnl.0000247274.21261.b4
↑ Alen J, Schade M, Wagener M, Christian F, Nordhoff S, Merla B, Dunkern TR, Bahrenberg G, Ratcliffe P. Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors. J Med Chem. 2019 Jun 25. doi: 10.1021/acs.jmedchem.9b00218. PMID:31244106 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00218

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6i6p"

@@ Line 3: / Line 3: @@
 <StructureSection load='6i6p' size='340' side='right'caption='[[6i6p]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6i6p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I6P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I6P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6i6p]] 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=6I6P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I6P 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=H4T:6-azaspiro[3.4]octan-6-yl-[2,4-bis(chloranyl)-6-oxidanyl-phenyl]methanone'>H4T</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=6i6p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i6p OCA], [http://pdbe.org/6i6p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6i6p RCSB], [http://www.ebi.ac.uk/pdbsum/6i6p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6i6p ProSAT]</span></td></tr>
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Alen, J]]

6i6p

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Current revision

SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 3

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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