4KAK

Crystal structure of human dihydrofolate reductase complexed with NADPH and 6-ethyl-5-[(3S)-3-[3-methoxy-5-(pyridine-4-yl)phenyl]but-1-yn-1-yl]pyrimidine-2,4-diamine (UCP1006)

4KAK の概要

• エントリーDOI: 10.2210/pdb4kak/pdb
• 関連するPDBエントリー: 4KBN 4KD7 4KEB 4KFJ
• 分子名称: Dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-ethyl-5-{(3R)-3-[3-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine, ... (6 entities in total)
• 機能のキーワード: oxidoreductase, 5, 6, 7, 8-tetrahydrofolate; nadp+; 7, 8-dihydrofolate, hydride shift, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 45327.45

構造登録者

Lamb, K.M.,Anderson, A.C. (登録日: 2013-04-22, 公開日: 2013-10-09, 最終更新日: 2023-09-20)

主引用文献

Lamb, K.M.,G-Dayanandan, N.,Wright, D.L.,Anderson, A.C.
Elucidating features that drive the design of selective antifolates using crystal structures of human dihydrofolate reductase.
Biochemistry, 52:7318-7326, 2013

PubMed Abstract: The pursuit of antimicrobial drugs that target dihydrofolate reductase (DHFR) exploits differences in sequence and dynamics between the pathogenic and human enzymes. Here, we present five crystal structures of human DHFR bound to a new class of antimicrobial agents, the propargyl-linked antifolates (PLAs), with a range of potency (IC50 values of 0.045-1.07 μM) for human DHFR. These structures reveal that interactions between the ligands and Asn 64, Phe 31, and Phe 34 are important for increased affinity for human DHFR and that loop residues 58-64 undergo ligand-induced conformational changes. The utility of these structural studies was demonstrated through the design of three new ligands that reduce the number of contacts with Asn 64, Phe 31, and Phe 34. Synthesis and evaluation show that one of the designed inhibitors exhibits the lowest affinity for human DHFR of any of the PLAs (2.64 μM). Comparisons of structures of human and Staphylococcus aureus DHFR bound to the same PLA reveal a conformational change in the ligand that enhances interactions with residues Phe 92 (Val 115 in huDHFR) and Ile 50 (Ile 60 in huDHFR) in S. aureus DHFR, yielding selectivity. Likewise, comparisons of human and Candida glabrata DHFR bound to the same ligand show that hydrophobic interactions with residues Ile 121 and Phe 66 (Val 115 and Asn 64 in human DHFR) yield selective inhibitors. The identification of residue substitutions that are important for selectivity and the observation of active site flexibility will help guide antimicrobial antifolate development for the inhibition of pathogenic species.

PubMed: 24053334
DOI: 10.1021/bi400852h

実験手法

X-RAY DIFFRACTION (1.8 Å)