2anq: Difference between revisions
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New page: left|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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[[Image:2anq.gif|left|200px]]<br /><applet load="2anq" size=" | [[Image:2anq.gif|left|200px]]<br /><applet load="2anq" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2anq, resolution 2.130Å" /> | caption="2anq, resolution 2.130Å" /> | ||
'''Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.'''<br /> | '''Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.'''<br /> | ||
==Overview== | ==Overview== | ||
Dihydrofolate reductase (DHFR) is a vital metabolic enzyme and thus a | 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== | ==About this Structure== | ||
2ANQ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with MN, NAP and C1A as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] Full crystallographic information is available from [http:// | 2ANQ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=MN:'>MN</scene>, <scene name='pdbligand=NAP:'>NAP</scene> and <scene name='pdbligand=C1A:'>C1A</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ANQ OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Brown, E | [[Category: Brown, E D.]] | ||
[[Category: Daigle, D | [[Category: Daigle, D M.]] | ||
[[Category: Hughes, D | [[Category: Hughes, D W.]] | ||
[[Category: Jackson, S | [[Category: Jackson, S G.]] | ||
[[Category: Junop, M | [[Category: Junop, M S.]] | ||
[[Category: Mayer, S.]] | [[Category: Mayer, S.]] | ||
[[Category: Organ, M.]] | [[Category: Organ, M.]] | ||
[[Category: Summerfield, R | [[Category: Summerfield, R L.]] | ||
[[Category: C1A]] | [[Category: C1A]] | ||
[[Category: MN]] | [[Category: MN]] | ||
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[[Category: protein inhibitor complex]] | [[Category: protein inhibitor complex]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:29:10 2008'' | ||
