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TitleStructure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin.
Journal, issue, pagesProc. Natl. Acad. Sci. U.S.A., Vol. 116, Issue 23, Page 11229-11234, Year 2019
Publish dateJun 4, 2019
AuthorsMarte Innselset Flydal / Martín Alcorlo-Pagés / Fredrik Gullaksen Johannessen / Siseth Martínez-Caballero / Lars Skjærven / Rafael Fernandez-Leiro / Aurora Martinez / Juan A Hermoso /
PubMed AbstractPhenylalanine hydroxylase (PAH) is a key enzyme in the catabolism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental ...Phenylalanine hydroxylase (PAH) is a key enzyme in the catabolism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental retardation if untreated. Some patients benefit from supplementation with a synthetic formulation of the cofactor tetrahydrobiopterin (BH) that partly acts as a pharmacological chaperone. Here we present structures of full-length human PAH (hPAH) both unbound and complexed with BH in the precatalytic state. Crystal structures, solved at 3.18-Å resolution, show the interactions between the cofactor and PAH, explaining the negative regulation exerted by BH BH forms several H-bonds with the N-terminal autoregulatory tail but is far from the catalytic Fe Upon BH binding a polar and salt-bridge interaction network links the three PAH domains, explaining the stability conferred by BH Importantly, BH binding modulates the interaction between subunits, providing information about PAH allostery. Moreover, we also show that the cryo-EM structure of hPAH in absence of BH reveals a highly dynamic conformation for the tetramers. Structural analyses of the hPAH:BH subunits revealed that the substrate-induced movement of Tyr138 into the active site could be coupled to the displacement of BH from the precatalytic toward the active conformation, a molecular mechanism that was supported by site-directed mutagenesis and targeted molecular dynamics simulations. Finally, comparison of the rat and human PAH structures show that hPAH is more dynamic, which is related to amino acid substitutions that enhance the flexibility of hPAH and may increase the susceptibility to PKU-associated mutations.
External linksPubMed:31118288 / Publisher's page
KeywordsOXIDOREDUCTASE / Tetrahydrobiopterin / amino acid hydroxylases / phenylketonuria / allosteric regulation / METAL BINDING PROTEIN / oxidoreductase / phenylalanine hydroxylase / allostery
MethodsEM (single particle) / X-ray diffraction
Resolution1.67 - 5 A
Structure data

EMDB-4605:
Human Phenylalanine Hydroxylase (hPAH) apo structure

PDB-6hpo:
Crystallographic structure of the catalytic domain of Human Phenylalanine Hydroxylase (hPAH CD) in complex with iron at 1.6 Angstrom

PDB-6hyc:
The structure of full-length human phenylalanine hydroxylase in complex with the cofactor and negative regulator tetrahydrobiopterin

Chemicals

ChemComp-FE:
FE (III) IONIron

ChemComp-HOH:
WATERWater

ChemComp-H4B:
5,6,7,8-TETRAHYDROBIOPTERINTetrahydrobiopterin

Source
  • homo sapiens (human)

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