PMID- 10331871
OWN - NLM
STAT- MEDLINE
DCOM- 19990603
LR  - 20131121
IS  - 1072-8368 (Print)
IS  - 1072-8368 (Linking)
VI  - 6
IP  - 5
DP  - 1999 May
TI  - Structural basis of autoregulation of phenylalanine hydroxylase.
PG  - 442-8
AB  - Phenylalanine hydroxylase converts phenylalanine to tyrosine, a rate-limiting
      step in phenylalanine catabolism and protein and neurotransmitter biosynthesis.
      It is tightly regulated by the substrates phenylalanine and tetrahydrobiopterin
      and by phosphorylation. We present the crystal structures of dephosphorylated and
      phosphorylated forms of a dimeric enzyme with catalytic and regulatory properties
      of the wild-type protein. The structures reveal a catalytic domain flexibly
      linked to a regulatory domain. The latter consists of an N-terminal
      autoregulatory sequence (containing Ser 16, which is the site of phosphorylation)
      that extends over the active site pocket, and an alpha-beta sandwich core that
      is, unexpectedly, structurally related to both pterin dehydratase and the
      regulatory domains of metabolic enzymes. Phosphorylation has no major structural 
      effects in the absence of phenylalanine, suggesting that phenylalanine and
      phosphorylation act in concert to activate the enzyme through a combination of
      intrasteric and possibly allosteric mechanisms.
FAU - Kobe, B
AU  - Kobe B
AD  - St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
      B.Kobe@medicine.unimelb.edu.au
FAU - Jennings, I G
AU  - Jennings IG
FAU - House, C M
AU  - House CM
FAU - Michell, B J
AU  - Michell BJ
FAU - Goodwill, K E
AU  - Goodwill KE
FAU - Santarsiero, B D
AU  - Santarsiero BD
FAU - Stevens, R C
AU  - Stevens RC
FAU - Cotton, R G
AU  - Cotton RG
FAU - Kemp, B E
AU  - Kemp BE
LA  - eng
SI  - PDB/1PHZ
SI  - PDB/2PHM
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Nat Struct Biol
JT  - Nature structural biology
JID - 9421566
RN  - 0 (Peptide Fragments)
RN  - 47E5O17Y3R (Phenylalanine)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.14.16.1 (Phenylalanine Hydroxylase)
SB  - IM
CIN - Nat Struct Biol. 1999 May;6(5):401-2. PMID: 10331859
MH  - Allosteric Regulation/drug effects
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites/genetics
MH  - Catalytic Domain/genetics
MH  - Crystallization
MH  - Crystallography, X-Ray
MH  - Dimerization
MH  - Evolution, Molecular
MH  - Humans
MH  - Mixed Function Oxygenases/chemistry
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Peptide Fragments/chemistry/genetics/metabolism
MH  - Phenylalanine/metabolism/pharmacology
MH  - Phenylalanine Hydroxylase/*chemistry/genetics/*metabolism
MH  - Phenylketonurias/enzymology/genetics
MH  - Phosphorylation
MH  - Protein Conformation
MH  - Rats
MH  - Sequence Homology, Amino Acid
EDAT- 1999/05/20 06:00
MHDA- 2001/03/23 10:01
CRDT- 1999/05/20 06:00
PHST- 1999/05/20 06:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/05/20 06:00 [entrez]
AID - 10.1038/8247 [doi]
PST - ppublish
SO  - Nat Struct Biol. 1999 May;6(5):442-8. doi: 10.1038/8247.