%0 Journal Article
%A Yajima, Shunsuke
%A Hara, Kodai
%A Sanders, John M.
%A Yin, Fenglin
%A Ohsawa, Kanju
%A Wiesner, Jochen
%A Jomaa, Hassan
%A Oldfield, Eric
%D 2004
%T Crystallographic Structures of Two
Bisphosphonate:1-Deoxyxylulose-5-Phosphate Reductoisomerase Complexes
%U https://acs.figshare.com/articles/journal_contribution/Crystallographic_Structures_of_Two_Bisphosphonate_1_Deoxyxylulose_5_Phosphate_Reductoisomerase_Complexes/3325696
%R 10.1021/ja040126m.s001
%2 https://ndownloader.figshare.com/files/5164480
%K bisphosphonates bind
%K sulfate ion
%K Crystallographic Structures
%K crystal structures
%K antimalarial drugs
%K phosphonate groups
%K EC
%K antiinfective agents
%K fosmidomycin binding site
%K DXR inhibitors
%K carboxylic acid groups
%X We have obtained the single-crystal X-ray crystallographic structures of the bisphosphonates [(1-isoquinolinylamino)methylene]-1,1-bisphosphonate and [[(5-chloro-2-pyridinyl)amino]methylene]-1,1-bisphosphonate, bound to the enzyme 1-deoxyxylulose-5-phosphate reductoisomerase (DXR, EC 1.1.1.267, also known as 2-C-methyl-d-erythritol-4-phosphate synthase), an important target for the development of antimalarial drugs. Our results indicate that both bisphosphonates bind into the fosmidomycin binding site. The aromatic groups are in a shallow hydrophobic pocket, and the phosphonate groups are involved in electrostatic interactions with Mg2+ or a cluster of carboxylic acid groups and lysine while the fosmidomycin phosphonate-binding site is occupied by a sulfate ion (as also observed in the DXR/NADP+ structure). The availability of these two new crystal structures opens up the possibility of the further development of bisphosphonates and related systems as DXR inhibitors and, potentially, as antiinfective agents.
%I ACS Publications