6usn

Co-crystal structure of SPR with compound 5Co-crystal structure of SPR with compound 5

Structural highlights

6usn is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.773Å
Ligands:	, , , ,
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

Sepiapterin reductase has been identified as a potential drug target for neuropathic and inflammatory pain. Virtual screening was executed against a publicly available x-ray crystal structure of sepiapterin reductase. A set of structurally diverse and potent sepiapterin reductase inhibitors was identified. This set of compounds with favorable ligand efficiency and lipophilic efficiency are tractable for further optimization. An SAR follow-up library was synthesized based on one of the virtual screening hits exploring SAR.

Virtual screening to identify potent sepiapterin reductase inhibitors.,Gao H, Schneider S, Andrews P, Wang K, Huang X, Sparling BA Bioorg Med Chem Lett. 2019 Nov 9:126793. doi: 10.1016/j.bmcl.2019.126793. PMID:31740247^[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
↑ Gao H, Schneider S, Andrews P, Wang K, Huang X, Sparling BA. Virtual screening to identify potent sepiapterin reductase inhibitors. Bioorg Med Chem Lett. 2019 Nov 9:126793. doi: 10.1016/j.bmcl.2019.126793. PMID:31740247 doi:http://dx.doi.org/10.1016/j.bmcl.2019.126793

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OCA

[1] 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

[2] 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

[3] 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

[4] Gao H, Schneider S, Andrews P, Wang K, Huang X, Sparling BA. Virtual screening to identify potent sepiapterin reductase inhibitors. Bioorg Med Chem Lett. 2019 Nov 9:126793. doi: 10.1016/j.bmcl.2019.126793. PMID:31740247 doi:http://dx.doi.org/10.1016/j.bmcl.2019.126793

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