2anq
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(New page: 200px<br /><applet load="2anq" size="450" color="white" frame="true" align="right" spinBox="true" caption="2anq, resolution 2.130Å" /> '''Crystal Structure o...)
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Revision as of 06:07, 21 November 2007
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Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.
Overview
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-benz, ene (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.
About this Structure
2ANQ is a Single protein structure of sequence from Escherichia coli with MN, NAP and C1A as ligands. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Full crystallographic information is available from OCA.
Reference
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., Summerfield RL, Daigle DM, Mayer S, Mallik D, Hughes DW, Jackson SG, Sulek M, Organ MG, Brown ED, Junop MS, J Med Chem. 2006 Nov 30;49(24):6977-86. PMID:17125251
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