3FUH

Leukotriene A4 hydrolase in complex with fragment 5-hydroxyindole and bestatin

Summary for 3FUH

• Entry DOI: 10.2210/pdb3fuh/pdb
• Related: 3FH7 3FTS 3FTU 3FTV 3FTW 3FTX 3FTY 3FTZ 3FU0 3FU3 3FU5 3FU6 3FUD 3FUE 3FUF 3FUI 3FUJ 3FUK 3FUL 3FUM 3FUN
• Descriptor: Leukotriene A-4 hydrolase, ZINC ION, YTTERBIUM (III) ION, ... (7 entities in total)
• Functional Keywords: leukotriene a4 hydrolase, lta4h, fragment crystallography, fragments of life, fol, alternative splicing, cytoplasm, hydrolase, leukotriene biosynthesis, metal-binding, metalloprotease, multifunctional enzyme, polymorphism, protease, zinc
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P09960
• Total number of polymer chains: 1
• Total formula weight: 70459.10

Authors

Davies, D.R. (deposition date: 2009-01-14, release date: 2009-07-28, Last modification date: 2023-09-06)

Primary citation

Davies, D.R.,Mamat, B.,Magnusson, O.T.,Christensen, J.,Haraldsson, M.H.,Mishra, R.,Pease, B.,Hansen, E.,Singh, J.,Zembower, D.,Kim, H.,Kiselyov, A.S.,Burgin, A.B.,Gurney, M.E.,Stewart, L.J.
Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.
J.Med.Chem., 52:4694-4715, 2009

PubMed Abstract: We describe a novel fragment library termed fragments of life (FOL) for structure-based drug discovery. The FOL library includes natural small molecules of life, derivatives thereof, and biaryl protein architecture mimetics. The choice of fragments facilitates the interrogation of protein active sites, allosteric binding sites, and protein-protein interaction surfaces for fragment binding. We screened the FOL library against leukotriene A4 hydrolase (LTA4H) by X-ray crystallography. A diverse set of fragments including derivatives of resveratrol, nicotinamide, and indole were identified as efficient ligands for LTA4H. These fragments were elaborated in a small number of synthetic cycles into potent inhibitors of LTA4H representing multiple novel chemotypes for modulating leukotriene biosynthesis. Analysis of the fragment-bound structures also showed that the fragments comprehensively recapitulated key chemical features and binding modes of several reported LTA4H inhibitors.

PubMed: 19618939
DOI: 10.1021/jm900259h

Experimental method

X-RAY DIFFRACTION (1.8 Å)