2BJU
Plasmepsin II complexed with a highly active achiral inhibitor
Summary for 2BJU
| Entry DOI | 10.2210/pdb2bju/pdb |
| Related | 1J8J 1LEE 1LF2 1LF3 1LF4 1M43 1ME6 1PFZ 1SME 1W6H 1W6I |
| Descriptor | PLASMEPSIN II, N-(R-CARBOXY-ETHYL)-ALPHA-(S)-(2-PHENYLETHYL) (3 entities in total) |
| Functional Keywords | plasmepsin, aspartic proteinase, drug design, malaria, aspartyl protease, glycoprotein, hydrolase, zymogen |
| Biological source | PLASMODIUM FALCIPARUM |
| Cellular location | Vacuole: P46925 |
| Total number of polymer chains | 1 |
| Total formula weight | 52727.99 |
| Authors | Prade, L.,Jones, A.F.,Boss, C.,Richards-Bildstein, S.,Meyer, S.,Binkert, C.,Bur, D. (deposition date: 2005-02-08, release date: 2005-04-18, Last modification date: 2024-11-06) |
| Primary citation | Prade, L.,Jones, A.F.,Boss, C.,Richard-Bildstein, S.,Meyer, S.,Binkert, C.,Bur, D. X-Ray Structure of Plasmepsin II Complexed with a Potent Achiral Inhibitor. J.Biol.Chem., 280:23837-, 2005 Cited by PubMed Abstract: The malaria parasite Plasmodium falciparum degrades host cell hemoglobin inside an acidic food vacuole during the blood stage of the infectious cycle. A number of aspartic proteinases called plasmepsins (PMs) have been identified to play important roles in this degradation process and therefore generated significant interest as new antimalarial targets. Several x-ray structures of PMII have been described previously, but thus far, structure-guided drug design has been hampered by the fact that only inhibitors comprising a statine moiety or derivatives thereof have been published. Our drug discovery efforts to find innovative, cheap, and easily synthesized inhibitors against aspartic proteinases yielded some highly potent non-peptidic achiral inhibitors. A highly resolved (1.6 A) x-ray structure of PMII is presented, featuring a potent achiral inhibitor in an unprecedented orientation, contacting the catalytic aspartates indirectly via the "catalytic" water. Major side chain rearrangements in the active site occur, which open up a new pocket and allow a new binding mode of the inhibitor. Moreover, a second inhibitor molecule could be located unambiguously in the active site of PMII. These newly obtained structural insights will further guide our attempts to improve compound properties eventually leading to the identification of molecules suitable as antimalarial drugs. PubMed: 15840589DOI: 10.1074/JBC.M501519200 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.56 Å) |
Structure validation
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