3ZWT
Structure of Human Dihydroorotate Dehydrogenase with a Bound Inhibitor
Summary for 3ZWT
| Entry DOI | 10.2210/pdb3zwt/pdb |
| Related | 1D3G 1D3H 2B0M 2BXV 2WV8 3ZWS |
| Descriptor | DIHYDROOROTATE DEHYDROGENASE (QUINONE), MITOCHONDRIAL, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (8 entities in total) |
| Functional Keywords | oxidoreductase |
| Biological source | HOMO SAPIENS (HUMAN) |
| Cellular location | Mitochondrion inner membrane; Single-pass membrane protein: Q02127 |
| Total number of polymer chains | 1 |
| Total formula weight | 41169.88 |
| Authors | Acklam, P.A.,Parsons, M.R. (deposition date: 2011-08-02, release date: 2012-06-27, Last modification date: 2023-12-20) |
| Primary citation | Bedingfield, P.T.P.,Cowen, D.,Acklam, P.A.,Cunningham, F.,Parsons, M.R.,Mcconkey, G.A.,Fishwick, C.W.G.,Johnson, A.P. Factors Influencing the Specificity of Inhibitor Binding to the Human and Malaria Parasite Dihydroorotate Dehydrogenases. J.Med.Chem., 55:5841-, 2012 Cited by PubMed Abstract: The de novo pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase is an emerging drug target for the treatment of malaria. In this context a key property of Plasmodium falciparum DHODH (PfDHODH) is that it can be selectively inhibited over its human homologue (HsDHODH). However, HsDHODH is also a validated drug target for autoimmune diseases such as arthritis. Here a series of novel inhibitors is described that includes compounds that switch specificity between the two enzymes as a result of small alterations in chemical structure. Structure-activity relationship (SAR), crystallography, docking, and mutagenesis studies are used to examine the binding modes of the compounds within the two enzymes and to reveal structural changes induced by inhibitor binding. Within this series, compounds with therapeutically relevant HsDHODH activity are described and their binding modes characterized using X-ray crystallography, which reveals a novel conformational shift within the inhibitor binding site. PubMed: 22621375DOI: 10.1021/JM300157N PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
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