2anq
From Proteopedia
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'''Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.''' | '''Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.''' | ||
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[[Category: Organ, M.]] | [[Category: Organ, M.]] | ||
[[Category: Summerfield, R L.]] | [[Category: Summerfield, R L.]] | ||
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| - | [[Category: | + | [[Category: Protein inhibitor complex]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 19:15:44 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 16:15, 3 May 2008
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. 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 Page seeded by OCA on Sat May 3 19:15:44 2008
