3KE1

Crystal structure of 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase from Burkholderia pseudomallei in complex with a fragment-nucleoside fusion D000161829

Summary for 3KE1

• Entry DOI: 10.2210/pdb3ke1/pdb
• Related: 3ieq 3ike 3ikf 3jvh 3k14 3k2x
• Descriptor: 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, ZINC ION, 5'-deoxy-5'-[(pyridin-4-ylcarbonyl)amino]cytidine, ... (5 entities in total)
• Functional Keywords: niaid, ssgcid, seattle structural genomics center for infectious disease, fragment crystallography, fbdd, fragment-based drug-design, nucleoside analog, d000161829, isoprene biosynthesis, lyase, metal-binding
• Biological source: Burkholderia pseudomallei (Pseudomonas pseudomallei)
• Total number of polymer chains: 3
• Total formula weight: 59738.63

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2009-10-23, release date: 2009-11-10, Last modification date: 2023-09-06)

Primary citation

Zhang, Z.,Jakkaraju, S.,Blain, J.,Gogol, K.,Zhao, L.,Hartley, R.C.,Karlsson, C.A.,Staker, B.L.,Edwards, T.E.,Stewart, L.J.,Myler, P.J.,Clare, M.,Begley, D.W.,Horn, J.R.,Hagen, T.J.
Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei.
Bioorg.Med.Chem.Lett., 8:e53851-e53851, 2013

PubMed Abstract: Published biological data suggest that the methyl erythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms. One highly conserved enzyme in the MEP pathway is 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment-bound complexes of IspF from Burkholderia pseudomallei were used to design and synthesize a series of molecules linking the cytidine moiety to different zinc pocket fragment binders. Testing by surface plasmon resonance (SPR) found one molecule in the series to possess binding affinity equal to that of cytidine diphosphate, despite lacking any metal-coordinating phosphate groups. Close inspection of the SPR data suggest different binding stoichiometries between IspF and test compounds. Crystallographic analysis shows important variations between the binding mode of one synthesized compound and the pose of the bound fragment from which it was designed. The binding modes of these molecules add to our structural knowledge base for IspF and suggest future refinements in this compound series.

PubMed: 24157367
DOI: 10.1016/j.bmcl.2013.09.101

Experimental method

X-RAY DIFFRACTION (2.05 Å)