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Human Cystathionine Gamma-Lyase in complex with DL-propargylglycine

PDB Code 3COG Target Class AA metabolic enzymes Target CTH Alias CTH, MGC9471 Disease Area/Function metabolism, neurobiology Date Deposited Mar 28 2008 Authors R. COLLINS, T.KARLBERG, L.TRESAUGUES, C.H.ARROWSMITH, H.BERGLUND, R.D.BUSAM, L.G.DAHLGREN, A.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, I.JOHANSSON, A.KALLAS, T.KOTENYOVA, L.LEHTIO, M.MOCHE, M.E.NILSSON, K. OLESEN, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, L.SVENSSON, A.G.THORSELL, S.VAN DEN BERG, J.WEIGELT, M.WELIN, M.WIKSTRÖM Related Structure 2NMP

About this structure

Cystathionine-γ-lyase (EC 4.4.1.1, CTH, cystathionase) is a pyridoxal-phosphate (PLP) dependent enzyme that catalyses the conversion of L-cystathionine to L-cysteine in the transulfuration pathway. Deficiency of CTH causes the autosomal recessive disease cystathioninemia. CTH can also convert L-cysteine to H2S. This gas transmitter is highly interesting from a medical perspective since it functions as a neuromodulator in the central nervous system and as a smooth muscle relaxant in the vascular system. It has also been suggested to be linked to several cardiovascular diseases, to (anti-) inflammatory responses and to gastric injury caused by non-steroidal anti-inflammatory drugs. H2S is produced in the liver, kidney, vascular system and gut by CTH and in the brain by cystathionine beta-synthetase (CBS). Overexpression of CTH inhibits cell proliferation, induces cell death and is linked to inflammation. DL-Propargylglycine (PPG) is one of CTH’s few known inhibitors and acts irreversibly. Here we present the crystal-structure of CTH in complex with PPG at 2.0Å resolution. The enzyme is crystallized as a tetramer with PLP observed covalently bound to Lys212 forming a Schiff base in three out of four active sites. Both monomers in the subunit interfaces contribute to the active site pocket. The inhibitor is observed bound to Tyr114 in three of the four subunits. The structurally revealed PPG binding mode differs from that postulated in the literature and should aid in the design of further, hopefully more potent and selective CTH inhibitors.

References

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