3HJ3
Crystal Structure of the ChTS-DHFR F207A Non-Active Site Mutant
Summary for 3HJ3
| Entry DOI | 10.2210/pdb3hj3/pdb |
| Descriptor | Chain A, crystal structure of Dhfr, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, 10-PROPARGYL-5,8-DIDEAZAFOLIC ACID, ... (6 entities in total) |
| Functional Keywords | ts, dhfr, enzyme, crossover, non-active site, oxidoreductase |
| Biological source | Cryptosporidium hominis |
| Total number of polymer chains | 4 |
| Total formula weight | 247902.10 |
| Authors | Anderson, K.S.,Martucci, W.E. (deposition date: 2009-05-20, release date: 2010-06-02, Last modification date: 2023-09-06) |
| Primary citation | Martucci, W.E.,Rodriguez, J.M.,Vargo, M.A.,Marr, M.,Hamilton, A.D.,Anderson, K.S. Exploring novel strategies for AIDS protozoal pathogens: alpha-helix mimetics targeting a key allosteric protein-protein interaction in C. hominis TS-DHFR. Medchemcomm, 4:1247-1256, 2013 Cited by PubMed Abstract: The bifunctional enzyme thymidylate synthase-dihydrofolate reductase (TS-DHFR) from the protozoal parasite is a potential molecular target for the design of antiparasitic therapies for AIDS-related opportunistic infections. The enzyme exists as a homodimer with each monomer containing a unique swap domain known as a "crossover helix" that binds in a cleft on the adjacent DHFR active site. This crossover helix is absent in species containing monofunctional forms of DHFR such as human. An in-depth understanding of protein-protein interactions between the crossover helix and adjacent DHFR active site that might modulate enzyme integrity or function would allow for insights into rational design of species-specific allosteric inhibitors. Mutational analysis coupled with structural studies and biophysical and kinetic characterization of crossover helix mutants identifies this domain as essential for full enzyme stability and catalytic activity, and pinpoints these effects to distinct faces of the crossover helix important in protein-protein interactions. Moreover, targeting this helical protein interaction with α-helix mimetics of the crossover helix leads to selective inhibition and destabilization of the TS-DHFR enzyme, thus validating this region as a new avenue to explore for species-specific inhibitor design. PubMed: 24324854DOI: 10.1039/C3MD00141E PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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