2ANQ

Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.

Summary for 2ANQ

• Entry DOI: 10.2210/pdb2anq/pdb
• Related: 2ANO
• Descriptor: Dihydrofolate reductase, MANGANESE (II) ION, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: dhfr, protein inhibitor complex, oxidoreductase
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 19242.13

Authors

Summerfield, R.L.,Daigle, D.M.,Mayer, S.,Jackson, S.G.,Organ, M.,Hughes, D.W.,Brown, E.D.,Junop, M.S. (deposition date: 2005-08-11, release date: 2006-07-25, Last modification date: 2024-02-14)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.13 Å)