3HJ3

Crystal Structure of the ChTS-DHFR F207A Non-Active Site Mutant

3HJ3 の概要

• エントリーDOI: 10.2210/pdb3hj3/pdb
• 分子名称: Chain A, crystal structure of Dhfr, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, 10-PROPARGYL-5,8-DIDEAZAFOLIC ACID, ... (6 entities in total)
• 機能のキーワード: ts, dhfr, enzyme, crossover, non-active site, oxidoreductase
• 由来する生物種: Cryptosporidium hominis
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 247902.10

構造登録者

Anderson, K.S.,Martucci, W.E. (登録日: 2009-05-20, 公開日: 2010-06-02, 最終更新日: 2023-09-06)

主引用文献

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

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: 24324854
DOI: 10.1039/C3MD00141E

実験手法

X-RAY DIFFRACTION (2.7 Å)