1MMK

Crystal structure of ternary complex of the catalytic domain of human phenylalanine hydroxylase ((FeII)) complexed with tetrahydrobiopterin and thienylalanine

Summary for 1MMK

• Entry DOI: 10.2210/pdb1mmk/pdb
• Related: 1J8T 1J8U 1KW0 1MMT
• Descriptor: Phenylalanine-4-hydroxylase, FE (II) ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: basket-arrangement, 13 alpha-helices, 8 beta-strands, ferrous iron, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38165.94

Authors

Andersen, O.A.,Flatmark, T.,Hough, E. (deposition date: 2002-09-04, release date: 2003-09-04, Last modification date: 2023-10-25)

Primary citation

Andersen, O.A.,Stokka, A.J.,Flatmark, T.,Hough, E.
2.0A resolution crystal structures of the ternary complexes of human phenylalanine hydroxylase catalytic domain with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine or L-norleucine: substrate specificity and molecular motions related to substrate binding
J.Mol.Biol., 333:747-757, 2003

PubMed Abstract: The crystal structures of the catalytic domain of human phenylalanine hydroxylase (hPheOH) in complex with the physiological cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)) and the substrate analogues 3-(2-thienyl)-L-alanine (THA) or L-norleucine (NLE) have been determined at 2.0A resolution. The ternary THA complex confirms a previous 2.5A structure, and the ternary NLE complex shows that similar large conformational changes occur on binding of NLE as those observed for THA. Both structures demonstrate that substrate binding triggers structural changes throughout the entire protomer, including the displacement of Tyr138 from a surface position to a buried position at the active site, with a maximum displacement of 20.7A for its hydroxyl group. Two hinge-bending regions, centred at Leu197 and Asn223, act in consort upon substrate binding to create further large structural changes for parts of the C terminus. Thus, THA/L-Phe binding to the active site is likely to represent the epicentre of the global conformational changes observed in the full-length tetrameric enzyme. The carboxyl and amino groups of THA and NLE are positioned identically in the two structures, supporting the conclusion that these groups are of key importance in substrate binding, thus explaining the broad non-physiological substrate specificity observed for artificially activated forms of the enzyme. However, the specific activity with NLE as the substrate was only about 5% of that with THA, which is explained by the different affinities of binding and different catalytic turnover.

PubMed: 14568534
DOI: 10.1016/j.jmb.2003.09.004

Experimental method

X-RAY DIFFRACTION (2 Å)