2ANO

Crystal structure of E.coli dihydrofolate reductase in complex with NADPH and the inhibitor MS-SH08-17

2ANO の概要

• エントリーDOI: 10.2210/pdb2ano/pdb
• 分子名称: Dihydrofolate reductase, MANGANESE (II) ION, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• 機能のキーワード: dhfr, protein inhibitor complex, oxidoreductase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19096.97

構造登録者

Summerfield, R.L.,Daigle, D.M.,Mayer, S.,Jackson, S.G.,Organ, M.,Hughes, D.W.,Brown, E.D.,Junop, M.S. (登録日: 2005-08-11, 公開日: 2006-07-25, 最終更新日: 2024-02-14)

主引用文献

Summerfield, R.L.,Daigle, D.M.,Mayer, S.,Mallik, D.,Hughes, D.W.,Jackson, S.G.,Sulek, M.,Organ, M.G.,Brown, E.D.,Junop, M.S.
A 2.13 A Structure of E. coli Dihydrofolate Reductase Bound to a Novel Competitive Inhibitor Reveals a New Binding Surface Involving the M20 Loop Region
J.Med.Chem., 49:6977-6986, 2006

PubMed Abstract: Dihydrofolate reductase (DHFR) is a vital metabolic enzyme and thus a clinically prominent target in the design of antimetabolites. In this work, we identify 1,4-bis-{[N-(1-imino-1-guanidino-methyl)]sulfanylmethyl}-3,6-dimethyl-benzene (compound 1) as the correct structure of the previously reported DHFR inhibitor 1,4-bis-{(iminothioureidomethyl)aminomethyl}-3,6-dimethyl-benzene (compound 2). The fact that compound 1 has an uncharacteristic structure for DHFR inhibitors, and an affinity (KI of 11.5 nM) comparable to potent inhibitors such as methotrexate and trimethoprim, made this inhibitor of interest for further analysis. We have conducted a characterization of the primary interactions of compound 1 and DHFR using a combination of X-ray structure and SAR analysis. The crystal structure of E. coli DHFR in complex with compound 1 and NADPH reveals that one portion of this inhibitor exploits a unique binding surface, the M20 loop. The importance of this interface was further confirmed by SAR analysis and additional structural characterization.

PubMed: 17125251
DOI: 10.1021/jm060570v

実験手法

X-RAY DIFFRACTION (2.68 Å)