3UPY

Crystal structure of the Brucella abortus enzyme catalyzing the first committed step of the methylerythritol 4-phosphate pathway.

Summary for 3UPY

• Entry DOI: 10.2210/pdb3upy/pdb
• Related: 3UPL
• Descriptor: Oxidoreductase, MAGNESIUM ION, 3-[FORMYL(HYDROXY)AMINO]PROPYLPHOSPHONIC ACID, ... (4 entities in total)
• Functional Keywords: rossmann fold, oxidoreductase, nadph binding
• Biological source: Brucella melitensis biovar Abortus 2308
• Total number of polymer chains: 2
• Total formula weight: 95560.83

Authors

Calisto, B.M.,Perez-Gil, J.,Fita, I.,Rodriguez-Concepcion, M. (deposition date: 2011-11-18, release date: 2012-03-28, Last modification date: 2023-09-13)

Primary citation

Perez-Gil, J.,Calisto, B.M.,Behrendt, C.,Kurz, T.,Fita, I.,Rodriguez-Concepcion, M.
Crystal structure of Brucella abortus deoxyxylulose-5-phosphate reductoisomerase-like (DRL) enzyme involved in isoprenoid biosynthesis.
J.Biol.Chem., 287:15803-15809, 2012

PubMed Abstract: Most bacteria use the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for the synthesis of their essential isoprenoid precursors. The absence of the MEP pathway in humans makes it a promising new target for the development of much needed new and safe antimicrobial drugs. However, bacteria show a remarkable metabolic plasticity for isoprenoid production. For example, the NADPH-dependent production of MEP from 1-deoxy-D-xylulose 5-phosphate in the first committed step of the MEP pathway is catalyzed by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in most bacteria, whereas an unrelated DXR-like (DRL) protein was recently found to catalyze the same reaction in some organisms, including the emerging human and animal pathogens Bartonella and Brucella. Here, we report the x-ray crystal structures of the Brucella abortus DRL enzyme in its apo form and in complex with the broad-spectrum antibiotic fosmidomycin solved to 1.5 and 1.8 Å resolution, respectively. DRL is a dimer, with each polypeptide folding into three distinct domains starting with the NADPH-binding domain, in resemblance to the structure of bacterial DXR enzymes. Other than that, DRL and DXR show a low structural relationship, with a different disposition of the domains and a topologically unrelated C-terminal domain. In particular, the active site of DRL presents a unique arrangement, suggesting that the design of drugs that would selectively inhibit DRL-harboring pathogens without affecting beneficial or innocuous bacteria harboring DXR should be feasible. As a proof of concept, we identified two strong DXR inhibitors that have virtually no effect on DRL activity.

PubMed: 22442144
DOI: 10.1074/jbc.M112.354811

Experimental method

X-RAY DIFFRACTION (1.8 Å)