1mmt

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spinqualitylabelsall models 1mmt, resolution 2.0Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of ternary complex of the catalytic domain of human phenylalanine hydroxylase (Fe(II)) complexed with tetrahydrobiopterin and norleucine

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known diseases associated with this structure: Hyperphenylalaninemia, mild OMIM:[261600], Phenylketonuria OMIM:[261600]

About this Structure

1MMT is a Single protein structure of sequence from Homo sapiens with FE2, SO4, H4B and NLE as ligands. Active as Phenylalanine 4-monooxygenase, with EC number 1.14.16.1 Full crystallographic information is available from OCA.

Reference

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., Andersen OA, Stokka AJ, Flatmark T, Hough E, J Mol Biol. 2003 Oct 31;333(4):747-57. PMID:14568534

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