title: Crystallographic structures of two bisphosphonate:1-deoxyxylulose-5-phosphate reductoisomerase complexes.
abstract: 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.
authors.affiliation: Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yajima
authors.forename: Kodai
authors.initials: K
authors.lastname: Hara
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Fenglin
authors.initials: F
authors.lastname: Yin
authors.forename: Kanju
authors.initials: K
authors.lastname: Ohsawa
authors.forename: Jochen
authors.initials: J
authors.lastname: Wiesner
authors.forename: Hassan
authors.initials: H
authors.lastname: Jomaa
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D005578:Fosfomycin; C024640:fosmidomycin; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases