4XWY
Crystal structure of human sepiapterin reductase in complex with an N-acetylserotinin analogue
Summary for 4XWY
| Entry DOI | 10.2210/pdb4xwy/pdb |
| Related | 4HWK 4J7U 4J7X |
| Descriptor | Sepiapterin reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, N-[2-(5-hydroxy-2-methyl-1H-indol-3-yl)ethyl]-2-methoxyacetamide, ... (5 entities in total) |
| Functional Keywords | oxidoreductase, inhibitor, complex |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cytoplasm: P35270 |
| Total number of polymer chains | 4 |
| Total formula weight | 124461.12 |
| Authors | Johnsson, K.,Hovius, R.,Gorszka, K.I.,Pojer, F. (deposition date: 2015-01-29, release date: 2015-07-01, Last modification date: 2024-01-10) |
| Primary citation | Latremoliere, A.,Latini, A.,Andrews, N.,Cronin, S.J.,Fujita, M.,Gorska, K.,Hovius, R.,Romero, C.,Chuaiphichai, S.,Painter, M.,Miracca, G.,Babaniyi, O.,Remor, A.P.,Duong, K.,Riva, P.,Barrett, L.B.,Ferreiros, N.,Naylor, A.,Penninger, J.M.,Tegeder, I.,Zhong, J.,Blagg, J.,Channon, K.M.,Johnsson, K.,Costigan, M.,Woolf, C.J. Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway. Neuron, 86:1393-1406, 2015 Cited by PubMed Abstract: Human genetic studies have revealed an association between GTP cyclohydrolase 1 polymorphisms, which decrease tetrahydrobiopterin (BH4) levels, and reduced pain in patients. We now show that excessive BH4 is produced in mice by both axotomized sensory neurons and macrophages infiltrating damaged nerves and inflamed tissue. Constitutive BH4 overproduction in sensory neurons increases pain sensitivity, whereas blocking BH4 production only in these cells reduces nerve injury-induced hypersensitivity without affecting nociceptive pain. To minimize risk of side effects, we targeted sepiapterin reductase (SPR), whose blockade allows minimal BH4 production through the BH4 salvage pathways. Using a structure-based design, we developed a potent SPR inhibitor and show that it reduces pain hypersensitivity effectively with a concomitant decrease in BH4 levels in target tissues, acting both on sensory neurons and macrophages, with no development of tolerance or adverse effects. Finally, we demonstrate that sepiapterin accumulation is a sensitive biomarker for SPR inhibition in vivo. PubMed: 26087165DOI: 10.1016/j.neuron.2015.05.033 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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