3HF8

Crystal structure of human tryoptophan hydroxylase type 1 with bound LP-533401 and Fe

Summary for 3HF8

• Entry DOI: 10.2210/pdb3hf8/pdb
• Related: 3HF6 3HFB
• Descriptor: Tryptophan 5-hydroxylase 1, FE (III) ION, 4-{2-amino-6-[(1R)-2,2,2-trifluoro-1-(3'-fluorobiphenyl-4-yl)ethoxy]pyrimidin-4-yl}-L-phenylalanine, ... (4 entities in total)
• Functional Keywords: tryoptophan hydroxylase type 1, iron, metal-binding, monooxygenase, oxidoreductase, phosphoprotein, serotonin biosynthesis
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 33870.24

Authors

Tari, L.W.,Swanson, R.V.,Hunter, M.J. (deposition date: 2009-05-11, release date: 2010-04-21, Last modification date: 2024-02-21)

Primary citation

Cianchetta, G.,Stouch, T.,Yu, W.,Shi, Z.C.,Tari, L.W.,Swanson, R.V.,Hunter, M.J.,Hoffman, I.D.,Liu, Q.
Mechanism of Inhibition of Novel Tryptophan Hydroxylase Inhibitors Revealed by Co-crystal Structures and Kinetic Analysis.
Curr Chem Genomics, 4:19-26, 2010

PubMed Abstract: Trytophan Hydroxylase Type I (TPH1), most abundantly expressed in the gastrointestinal tract, initiates the synthesis of serotonin by catalyzing hydroxylation of tryptophan in the presence of biopterin and oxygen. We have previously described three series of novel, periphery-specific TPH1 inhibitors that selectively deplete serotonin in the gastrointestinal tract. We have now determined co-crystal structures of TPH1 with three of these inhibitors at high resolution. Analysis of the structural data showed that each of the three inhibitors fills the tryptophan binding pocket of TPH1 without reaching into the binding site of the cofactor pterin, and induces major conformational changes of the enzyme. The enzyme-inhibitor complexes assume a compact conformation that is similar to the one in tryptophan complex. Kinetic analysis showed that all three inhibitors are competitive versus the substrate tryptophan, consistent with the structural data that the compounds occupy the tryptophan binding site. On the other hand, all three inhibitors appear to be uncompetitive versus the cofactor 6-methyltetrahydropterin, which is not only consistent with the structural data but also indicate that the hydroxylation reaction follows an ordered binding mechanism in which a productive complex is formed only if tryptophan binds only after pterin, similar to the kinetic mechanisms of tyrosine and phenylalanine hydroxylase.

PubMed: 20556201
DOI: 10.2174/1875397301004010019

Experimental method

X-RAY DIFFRACTION (1.85 Å)