3GN1

Structure of Pteridine Reductase 1 (PTR1) from TRYPANOSOMA BRUCEI in ternary complex with cofactor (NADP+) and inhibitor (DDD00067116)

3GN1 の概要

• エントリーDOI: 10.2210/pdb3gn1/pdb
• 関連するPDBエントリー: 3BMC 3BMD 3BME 3BMF 3BMG 3BMH 3GN2
• 分子名称: Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1H-benzimidazol-2-amine, ... (5 entities in total)
• 機能のキーワード: pteridine reductase, ptr1, trypanosoma brucei, short chain dehydrogenase, inhibitor, oxidoreductase
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 126234.31

構造登録者

Tulloch, L.B.,Brenk, R.,Hunter, W.N. (登録日: 2009-03-16, 公開日: 2009-12-29, 最終更新日: 2025-03-26)

主引用文献

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

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: 19527033
DOI: 10.1021/jm900414x

実験手法

X-RAY DIFFRACTION (2 Å)