3GN2
Structure of Pteridine Reductase 1 (PTR1) from TRYPANOSOMA BRUCEI in ternary complex with cofactor (NADP+) and inhibitor (DDD00066730)
Summary for 3GN2
| Entry DOI | 10.2210/pdb3gn2/pdb |
| Related | 3BMC 3BMD 3BME 3BMF 3BMG 3BMH 3GN1 |
| Descriptor | Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1-(3,4-dichlorobenzyl)-1H-benzimidazol-2-amine, ... (5 entities in total) |
| Functional Keywords | pteridine reductase, ptr1, trypanosoma brucei, short chain dehydrogenase, inhibitor, oxidoreductase |
| Biological source | Trypanosoma brucei brucei |
| Total number of polymer chains | 4 |
| Total formula weight | 127172.64 |
| Authors | Tulloch, L.B.,Brenk, R.,Hunter, W.N. (deposition date: 2009-03-16, release date: 2009-12-29, Last modification date: 2024-02-21) |
| Primary citation | Mpamhanga, C.P.,Spinks, D.,Tulloch, L.B.,Shanks, E.J.,Robinson, D.A.,Collie, I.T.,Fairlamb, A.H.,Wyatt, P.G.,Frearson, J.A.,Hunter, W.N.,Gilbert, I.H.,Brenk, R. One scaffold, three binding modes: novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening. J.Med.Chem., 52:4454-4465, 2009 Cited by PubMed Abstract: The enzyme pteridine reductase 1 (PTR1) is a potential target for new compounds to treat human African trypanosomiasis. A virtual screening campaign for fragments inhibiting PTR1 was carried out. Two novel chemical series were identified containing aminobenzothiazole and aminobenzimidazole scaffolds, respectively. One of the hits (2-amino-6-chloro-benzimidazole) was subjected to crystal structure analysis and a high resolution crystal structure in complex with PTR1 was obtained, confirming the predicted binding mode. However, the crystal structures of two analogues (2-amino-benzimidazole and 1-(3,4-dichloro-benzyl)-2-amino-benzimidazole) in complex with PTR1 revealed two alternative binding modes. In these complexes, previously unobserved protein movements and water-mediated protein-ligand contacts occurred, which prohibited a correct prediction of the binding modes. On the basis of the alternative binding mode of 1-(3,4-dichloro-benzyl)-2-amino-benzimidazole, derivatives were designed and selective PTR1 inhibitors with low nanomolar potency and favorable physicochemical properties were obtained. PubMed: 19527033DOI: 10.1021/jm900414x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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