MF7000227 SurE (Coxiella burnetii) 3ty2 X-ray 1.89 Homodimer Coxiella burnetii 26033498 Franklin MC, Cheung J, Rudolph MJ, Burshteyn F, Cassidy M, Gary E, Hillerich B, Yao ZK, Carlier PR, Totrov M, Love JD Proteins 2015 12 83 2124-36 Coxiella burnetii is a highly infectious bacterium and potential agent of bioterrorism. However, it has not been studied as extensively as other biological agents, and very few of its proteins have been structurally characterized. To address this situation, we undertook a study of critical metabolic enzymes in C. burnetii that have great potential as drug targets. We used high-throughput techniques to produce novel crystal structures of 48 of these proteins. We selected one protein, C. burnetii dihydrofolate reductase (CbDHFR), for additional work to demonstrate the value of these structures for structure-based drug design. This enzyme's structure reveals a feature in the substrate binding groove that is different between CbDHFR and human dihydrofolate reductase (hDHFR). We then identified a compound by in silico screening that exploits this binding groove difference, and demonstrated that this compound inhibits CbDHFR with at least 25-fold greater potency than hDHFR. Since this binding groove feature is shared by many other prokaryotes, the compound identified could form the basis of a novel antibacterial agent effective against a broad spectrum of pathogenic bacteria. GO:0008254 3'-nucleotidase activity GO:0008253 5'-nucleotidase activity GO:0004309 exopolyphosphatase activity GO:0046872 metal ion binding GO:0000166 nucleotide binding GO:0106411 XMP 5'-nucleosidase activity GO:0005737 cytoplasm 2 1 Homooligomeric enzymes Homodimeric enzymes All chains according to the most probable oligomerization state stored in PDBe were considered. A 5'-nucleotidase SurE Coxiella burnetii Q9KI21 8 258 97% MKKTATPKLRLLLSNDDGVYAKGLAILAKTLADLGEVDVVAPDRNRSGASNSLTLNAPLHIKNLENGMISVEGTPTDCVHLAITGVLPEMPDMVVAGINAGPNLGDDVWYSGTVAAAMEGRFLGLPALAVSLGGELFRYYETAAKVVYQLIQRIEKDPLPPSTILNINVPDLPYEELKGFEVTRLGTRHRAEPTIRQIDPRGHPIYWVGAAGPEQDSGPGTDFFAMNHHCVSITPLRVDLTHYEAFDQLASWVKRLEM 258 secondary structure helix 24 35 secondary structure helix 77 86 secondary structure helix 107 113 secondary structure helix 114 123 secondary structure helix 142 160 secondary structure helix 176 180 secondary structure helix 224 231 secondary structure helix 245 247 secondary structure helix 248 260 secondary structure strand 13 17 secondary structure strand 39 45 secondary structure strand 62 66 secondary structure strand 72 74 secondary structure strand 96 103 secondary structure strand 130 135 secondary structure strand 167 172 secondary structure strand 182 185 secondary structure strand 198 201 secondary structure strand 207 210 secondary structure strand 233 238 pfam PF01975 Survival protein SurE 12 190 B 5'-nucleotidase SurE Coxiella burnetii Q9KI21 8 258 97% MKKTATPKLRLLLSNDDGVYAKGLAILAKTLADLGEVDVVAPDRNRSGASNSLTLNAPLHIKNLENGMISVEGTPTDCVHLAITGVLPEMPDMVVAGINAGPNLGDDVWYSGTVAAAMEGRFLGLPALAVSLGGELFRYYETAAKVVYQLIQRIEKDPLPPSTILNINVPDLPYEELKGFEVTRLGTRHRAEPTIRQIDPRGHPIYWVGAAGPEQDSGPGTDFFAMNHHCVSITPLRVDLTHYEAFDQLASWVKRLEM 258 secondary structure helix 24 35 secondary structure helix 77 86 secondary structure helix 107 113 secondary structure helix 114 123 secondary structure helix 124 126 secondary structure helix 142 160 secondary structure helix 176 180 secondary structure helix 224 231 secondary structure helix 245 247 secondary structure helix 248 258 secondary structure helix 259 261 secondary structure strand 13 17 secondary structure strand 39 45 secondary structure strand 62 66 secondary structure strand 72 74 secondary structure strand 96 103 secondary structure strand 130 135 secondary structure strand 167 172 secondary structure strand 183 185 secondary structure strand 198 201 secondary structure strand 207 210 secondary structure strand 234 239 pfam PF01975 Survival protein SurE 12 190 Direct evidence The full structure participates in mutual synergistic folding. Survival protein SurE Two-state thermal unfolding (PMID:23409101). Domain-swapped dimer with extensive swap region and large dimer interface. Dimeric in solution (gel filtration, DLS). A N/A B N/A MF7000821 MF7000221 MF7000222 MF7000224 MF7000227 MF7000223 MF7000225 MF7000226