1KMV

HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND (Z)-6-(2-[2,5-DIMETHOXYPHENYL]ETHEN-1-YL)-2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINE (SRI-9662), A LIPOPHILIC ANTIFOLATE

1KMV の概要

• エントリーDOI: 10.2210/pdb1kmv/pdb
• 関連するPDBエントリー: 1KMS
• 分子名称: DIHYDROFOLATE REDUCTASE, SULFATE ION, (Z)-6-(2-[2,5-DIMETHOXYPHENYL]ETHEN-1-YL)-2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINE, ... (6 entities in total)
• 機能のキーワード: oxidoreductase, antiparasitic drugs, reductase, lipophilic antifolates
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22606.52

構造登録者

Klon, A.E.,Heroux, A.,Ross, L.J.,Pathak, V.,Johnson, C.A.,Piper, J.R.,Borhani, D.W. (登録日: 2001-12-17, 公開日: 2002-07-10, 最終更新日: 2024-04-03)

主引用文献

Klon, A.E.,Heroux, A.,Ross, L.J.,Pathak, V.,Johnson, C.A.,Piper, J.R.,Borhani, D.W.
Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution.
J.Mol.Biol., 320:677-693, 2002

PubMed Abstract: The crystal structures of two human dihydrofolate reductase (hDHFR) ternary complexes, each with bound NADPH cofactor and a lipophilic antifolate inhibitor, have been determined at atomic resolution. The potent inhibitors 6-([5-quinolylamino]methyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (SRI-9439) and (Z)-6-(2-[2,5-dimethoxyphenyl]ethen-1-yl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (SRI-9662) were developed at Southern Research Institute against Toxoplasma gondii DHFR-thymidylate synthase. The 5-deazapteridine ring of each inhibitor adopts an unusual puckered conformation that enables the formation of identical contacts in the active site. Conversely, the quinoline and dimethoxybenzene moieties exhibit distinct binding characteristics that account for the differences in inhibitory activity. In both structures, a salt-bridge is formed between Arg70 in the active site and Glu44 from a symmetry-related molecule in the crystal lattice that mimics the binding of methotrexate to DHFR.

PubMed: 12096917
DOI: 10.1016/S0022-2836(02)00469-2

実験手法

X-RAY DIFFRACTION (1.05 Å)