1dmw
From Proteopedia
|
CRYSTAL STRUCTURE OF DOUBLE TRUNCATED HUMAN PHENYLALANINE HYDROXYLASE WITH BOUND 7,8-DIHYDRO-L-BIOPTERIN
Contents |
Overview
The crystal structure of the dimeric catalytic domain (residues 118-424), of human PheOH (hPheOH), cocrystallized with the oxidized form of the, cofactor (7,8-dihydro-L-biopterin, BH(2)), has been determined at 2.0 A, resolution. The pterin binds in the second coordination sphere of the, catalytic iron (the C4a atom is 6.1 A away), and interacts through several, hydrogen bonds to two water molecules coordinated to the iron, as well as, to the main chain carbonyl oxygens of Ala322, Gly247, and Leu249 and the, main chain amide of Leu249. Some important conformational changes are seen, in the active site upon pterin binding. The loop between residues 245 and, 250 moves in the direction of the iron, and thus allows for several, important hydrogen bonds to the pterin ring to be formed. The pterin, cofactor is in an ideal orientation for dioxygen to bind in a bridging, position between the iron and the pterin. The pterin ring forms an, aromatic pi-stacking interaction with Phe254, and Tyr325 contributes to, the positioning of the pterin ring and its dihydroxypropyl side chain by, hydrophobic interactions. Of particular interest in the hPheOH x BH(2), binary complex structure is the finding that Glu286 hydrogen bonds to one, of the water molecules coordinated to the iron as well as to a water, molecule which hydrogen bonds to N3 of the pterin ring. Site-specific, mutations of Glu286 (E286A and E286Q), Phe254 (F254A and F254L), and, Tyr325 (Y325F) have confirmed the important contribution of Glu286 and, Phe254 to the normal positioning of the pterin cofactor and catalytic, activity of hPheOH. Tyr325 also contributes to the correct positioning of, the pterin, but has no direct function in the catalytic reaction, in, agreement with the results obtained with rat TyrOH [Daubner, S. C., and, Fitzpatrick, P. F. (1998) Biochemistry 37, 16440-16444]. Superposition of, the binary hPheOH.BH(2) complex onto the crystal structure of the, ligand-free rat PheOH (which contains the regulatory and catalytic, domains) [Kobe, B., Jennings, I. G., House, C. M., Michell, B. J., Goodwill, K. E., Santarsiero, B. D., Stevens, R. C., Cotton, R. G. H., and, Kemp, B. E. (1999) Nat. Struct. Biol. 6, 442-448] reveals that the, C2'-hydroxyl group of BH(2) is sufficiently close to form hydrogen bonds, to Ser23 in the regulatory domain. Similar interactions are seen with the, hPheOH.adrenaline complex and Ser23. These interactions suggest a, structural explanation for the specific regulatory properties of the, dihydroxypropyl side chain of BH(4) (negative effector) in the full-length, enzyme in terms of phosphorylation of Ser16 and activation by L-Phe.
Disease
Known diseases associated with this structure: Hyperphenylalaninemia, mild OMIM:[261600], Phenylketonuria OMIM:[261600]
About this Structure
1DMW is a Single protein structure of sequence from Homo sapiens with FE and HBI as ligands. The following page contains interesting information on the relation of 1DMW with [Phenylalanine Hydroxylase]. Active as Phenylalanine 4-monooxygenase, with EC number 1.14.16.1 Full crystallographic information is available from OCA.
Reference
Crystal structure and site-specific mutagenesis of pterin-bound human phenylalanine hydroxylase., Erlandsen H, Bjorgo E, Flatmark T, Stevens RC, Biochemistry. 2000 Mar 7;39(9):2208-17. PMID:10694386
Page seeded by OCA on Mon Nov 12 16:33:56 2007
