PDBsum entry 1wpl

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protein ligands metals Protein-protein interface(s) links
Hydrolase/protein binding PDB id
Protein chains
(+ 4 more) 194 a.a. *
(+ 4 more) 84 a.a. *
HBI ×10
3PO ×10
_NA ×10
_ZN ×10
Waters ×230
* Residue conservation analysis
PDB id:
Name: Hydrolase/protein binding
Title: Crystal structure of the inhibitory form of rat gtp cyclohydrolase i/gfrp complex
Structure: Gtp cyclohydrolase i. Chain: a, b, c, d, e, f, g, h, i, j. Synonym: gtp-ch-i. Engineered: yes. Gtp cyclohydrolase i feedback regulatory protein. Chain: k, l, m, n, o, p, q, r, s, t. Synonym: p35. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Not given
2.80Å     R-factor:   0.207     R-free:   0.233
Authors: N.Maita,K.Hatakeyama,K.Okada,T.Hakoshima
Key ref:
N.Maita et al. (2004). Structural basis of biopterin-induced inhibition of GTP cyclohydrolase I by GFRP, its feedback regulatory protein. J Biol Chem, 279, 51534-51540. PubMed id: 15448133 DOI: 10.1074/jbc.M409440200
08-Sep-04     Release date:   28-Sep-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P22288  (GCH1_RAT) -  GTP cyclohydrolase 1
241 a.a.
194 a.a.
Protein chains
Pfam   ArchSchema ?
P70552  (GFRP_RAT) -  GTP cyclohydrolase 1 feedback regulatory protein
84 a.a.
84 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D, E, F, G, H, I, J: E.C.  - Gtp cyclohydrolase i.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Folate Biosynthesis (early stages)
      Reaction: GTP + H2O = formate + 2-amino-4-hydroxy-6-(erythro-1,2,3- trihydroxypropyl)-dihydropteridine triphosphate
Bound ligand (Het Group name = HBI)
matches with 53.00% similarity
+ H(2)O
= formate
+ 2-amino-4-hydroxy-6-(erythro-1,2,3- trihydroxypropyl)-dihydropteridine triphosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     protein complex   10 terms 
  Biological process     metabolic process   23 terms 
  Biochemical function     catalytic activity     16 terms  


    Added reference    
DOI no: 10.1074/jbc.M409440200 J Biol Chem 279:51534-51540 (2004)
PubMed id: 15448133  
Structural basis of biopterin-induced inhibition of GTP cyclohydrolase I by GFRP, its feedback regulatory protein.
N.Maita, K.Hatakeyama, K.Okada, T.Hakoshima.
GTP cyclohydrolase I (GTPCHI) is the rate-limiting enzyme involved in the biosynthesis of tetrahydrobiopterin, a key cofactor necessary for nitric oxide synthase and for the hydroxylases that are involved in the production of catecholamines and serotonin. In animals, the GTPCHI feedback regulatory protein (GFRP) binds GTPCHI to mediate feed-forward activation of GTPCHI activity in the presence of phenylalanine, whereas it induces feedback inhibition of enzyme activity in the presence of biopterin. Here, we have reported the crystal structure of the biopterin-induced inhibitory complex of GTPCHI and GFRP and compared it with the previously reported phenylalanine-induced stimulatory complex. The structure reveals five biopterin molecules located at each interface between GTPCHI and GFRP. Induced fitting structural changes by the biopterin binding expand large conformational changes in GTPCHI peptide segments forming the active site, resulting in inhibition of the activity. By locating 3,4-dihydroxy-phenylalanine-responsive dystonia mutations in the complex structure, we found mutations that may possibly disturb the GFRP-mediated regulation of GTPCHI.
  Selected figure(s)  
Figure 4.
FIG. 4. BH[2]-induced structural changes in the active site. A, comparison of the biopterin-binding sites in the inhibitory (left) and stimulatory (right) complexes. The binding site consists of residues from GTPCHI subunits A (green) and B (yellow). BH[2] is shown in magenta in the inhibitory complex (left). Broken lines indicate hydrogen bonds. Two water molecules (red balls) involved in BH[2] recognition are also shown with labels, W1 and W2 that correspond to WAT1 and WAT2 in Fig. 2B, respectively. B and C, comparison of the active sites in the stimulatory (red) and the inhibitory (green) complexes. Two pentamers were superimposed by fitting C[ ]carbon atoms of the inner -strands, forming a -barrel in the GTPCHI pentamer rings. The GTP molecule from the E. coli GTPCHI·GTP structure (Protein Data Bank accession code 1A9C [PDB] ) is fitted to the structures. Panel C is a 90° rotated view from panel B. D, the molecular surfaces of the active sites in the inhibitory (left) and stimulatory (right) complexes. The GTP molecule from the E. coli GTPCHI·GTP complex is overlaid.
Figure 5.
FIG. 5. Mutations mapped on the GTPCHI structure. Missense mutations identified in DRD patients. Residue numbers were derived from human GTPCHI to rat GTPCHI and mapped onto the rat GTPCHI monomer structure from the inhibitory complex. Mutated residues are shown as colored balls: residues involved in BH[2] binding (cyan) and GFRP binding (green) contact to the opposite ring (blue), stabilizing the tertiary structure (magenta) and those located at the active site (red). Location and environment of each mutated residue are summarized in Table II.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 51534-51540) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19101819 B.Chavan, W.Beazley, J.M.Wood, H.Rokos, H.Ichinose, and K.U.Schallreuter (2009).
H(2)O(2) increases de novo synthesis of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin via GTP cyclohydrolase I and its feedback regulatory protein in vitiligo.
  J Inherit Metab Dis, 32, 86-94.  
19767425 B.Sankaran, S.A.Bonnett, K.Shah, S.Gabriel, R.Reddy, P.Schimmel, D.A.Rodionov, Crécy-Lagard, J.D.Helmann, D.Iwata-Reuyl, and M.A.Swairjo (2009).
Zinc-independent folate biosynthesis: genetic, biochemical, and structural investigations reveal new metal dependence for GTP cyclohydrolase IB.
  J Bacteriol, 191, 6936-6949.
PDB codes: 3d1t 3d2o
19762783 J.Du, N.Wei, H.Xu, Y.Ge, J.Vásquez-Vivar, T.Guan, K.T.Oldham, K.A.Pritchard, and Y.Shi (2009).
Identification and functional characterization of phosphorylation sites on GTP cyclohydrolase I.
  Arterioscler Thromb Vasc Biol, 29, 2161-2168.  
19628033 J.Vásquez-Vivar (2009).
Tetrahydrobiopterin, superoxide, and vascular dysfunction.
  Free Radic Biol Med, 47, 1108-1119.  
18634867 J.Vásquez-Vivar, J.Whitsett, I.Ionova, E.Konorev, J.Zielonka, B.Kalyanaraman, Y.Shi, and G.M.Pieper (2008).
Cytokines and lipopolysaccharides induce inducible nitric oxide synthase but not enzyme activity in adult rat cardiomyocytes.
  Free Radic Biol Med, 45, 994.  
18285800 X.O.Breakefield, A.J.Blood, Y.Li, M.Hallett, P.I.Hanson, and D.G.Standaert (2008).
The pathophysiological basis of dystonias.
  Nat Rev Neurosci, 9, 222-234.  
17191137 R.H.Foxton, J.M.Land, and S.J.Heales (2007).
Tetrahydrobiopterin availability in Parkinson's and Alzheimer's disease; potential pathogenic mechanisms.
  Neurochem Res, 32, 751-756.  
16778797 B.Chavan, J.M.Gillbro, H.Rokos, and K.U.Schallreuter (2006).
GTP cyclohydrolase feedback regulatory protein controls cofactor 6-tetrahydrobiopterin synthesis in the cytosol and in the nucleus of epidermal keratinocytes and melanocytes.
  J Invest Dermatol, 126, 2481-2489.  
16360951 R.Futahashi, and H.Fujiwara (2006).
Expression of one isoform of GTP cyclohydrolase I coincides with the larval black markings of the swallowtail butterfly, Papilio xuthus.
  Insect Biochem Mol Biol, 36, 63-70.  
16010344 M.Fischer, and A.Bacher (2005).
Biosynthesis of flavocoenzymes.
  Nat Prod Rep, 22, 324-350.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.