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Prostaglandin-H2 D-isomerase

PDB Code 2WWP Target Class Miscellaneous Target PTGDS Alias n/a Disease Area/Function signalling Date Deposited Oct 26 2009 Authors A.K. ROOS, TRESAUGUES, L., ARROWSMITH, C.H., BERGLUND, H., BOUNTRA, C., COLLINS, R., EDWARDS, A.M., FLODIN, S., FLORES, A., GRASLUND, S., HAMMARSTROM, M., JOHANSSON, A., JOHANSSON, I., KALLAS, A., KARLBERG, T., KOTYENOVA, T., KOTZCH, A., KRAULIS, P., MARKOVA, N., MOCHE, M., NIELSEN, T.K., NYMAN, T., PERSSON, C., SCHULER, H., SCHUTZ, P., SIPONEN, M.I., SVENSSON, L., THORSELL, A.G., VAN DEN BERG, S., WAHLBERG, E., WEIGELT, J., WELIN, M., WISNIEWSKA, M., NORDLUND, P.

About this structure

Lipocalin type prostaglandin D synthase (PTGDS) catalyses the conversion of prostaglandin (PG)D2 into PGH2 [1]. It is the only enzyme in the lipocalin type protein family, members of which mainly act as binding proteins. PTGDS is involved in several CNS functions such as pain regulation and non-rapid eye movement sleep. Apart from its enzymatic activity it has also been shown to bind various small, lipophilic compounds such as retinoic acid, bilirubin and thyroid hormone [2]. It is possible that this second function helps the cell get rid of harmful hydrophobic compounds. The protein has been localised to the endoplasm reticulum, golgi apparatus, cell membrane and is also secreted.

We have solved the human PTGDS to 2 Å resolution with two molecules in the asymmetric unit. The coordinates and experimental data have been deposited with the protein data bank under the accession code 2WWP. The monomer structure is very similar to the mouse counterpart with 75% sequence identity although the interactions between protein molecules are not the same. Our structure also includes the catalytic cysteine, which in the mouse structure has been mutated to an alanine [2].

The overall fold of PTGDS is a lipocalin type beta barrel with a large central, mainly hydrophobic, cavity. The active site is located in an upper compartment, where the catalytic cysteine (Cys65) is found close to three serines thought to play a role in catalysis. Our PTGDS crystals were grown in the presence of the prostaglandin substrate analog 9,11-Dideoxy-9α,11α-epoxymethanoprostaglandin F2α (D400). Unfortunately no density for the ligand can be seen. The catalytic cysteine has density supporting a double conformation and the helix preceding the catalytic cysteine is disordered, possibly due to movements caused by the substrate analog partially binding to the protein.

References

  1. Urade, Y., and Hayaishi, O. (2000) Biochim. Biophys. Acta 1482, 259–271. PubMed 11058767
  2. Kumasaka T., Aritake K., Ago H., Irikura D., Tsurumura T., Yamamoto M., Miyano M., Urade Y., Hayaishi O. (2009) J. Biol. Chem. 284, 22344–22352. PubMed 19546224