PDBsum entry 6i6f

Oxidoreductase

PDB id: 6i6f

Contents

Protein chains

265 a.a.

Ligands

NAP ×2

H4E

EDO ×13

Waters ×210

PDB id:

6i6f

Name:

Oxidoreductase

Title:

Sepiapterin reductase in complex with compound 1

Structure:

Sepiapterin reductase. Chain: a, b. Synonym: spr. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: spr. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

1.94Å R-factor: 0.193 R-free: 0.232

Authors:

J.Alen,M.Schade,M.Wagener,M.Blaesse

Key ref:

J.Alen et al. (2019). Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors. J Med Chem, 62, 6391-6397. PubMed id: 31244106 DOI: 10.1021/acs.jmedchem.9b00218

Date:

15-Nov-18 Release date: 10-Jul-19

Protein chains

P35270  (SPRE_HUMAN) -  Sepiapterin reductase from Homo sapiens

Seq: 261 a.a.

Struc: 265 a.a.

Enzyme reactions

• Enzyme class: E.C.1.1.1.153 - sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming).
• Pathway: Biopterin Biosynthesis
• Reaction:
  1. L-erythro-7,8-dihydrobiopterin + NADP⁺ = L-sepiapterin + NADPH + H⁺
  2. (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + 2 NADP⁺ = 6-pyruvoyl- 5,6,7,8-tetrahydropterin + 2 NADPH + 2 H⁺

L-erythro-7,8-dihydrobiopterin + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = L-sepiapterin + NADPH + H(+)

(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + 2 × NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 6-pyruvoyl- 5,6,7,8-tetrahydropterin + 2 × NADPH + 2 × H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jmedchem.9b00218

J Med Chem 62:6391-6397 (2019)

PubMed id: 31244106

Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors.

J.Alen, M.Schade, M.Wagener, F.Christian, S.Nordhoff, B.Merla, T.R.Dunkern, G.Bahrenberg, P.Ratcliffe.

ABSTRACT

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 ¹⁹F 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.