2anq
From Proteopedia
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| - | [[Image:2anq.gif|left|200px]] | + | [[Image:2anq.gif|left|200px]] |
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| - | '''Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.''' | + | {{Structure |
| + | |PDB= 2anq |SIZE=350|CAPTION= <scene name='initialview01'>2anq</scene>, resolution 2.130Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene> and <scene name='pdbligand=C1A:1,4-BIS-{[N-(1-IMINO-1GUANIDINO-METHYL)]SULFANYLMETHYL}-3,6-DIMETHYL-BENZENE'>C1A</scene> | ||
| + | |ACTIVITY= [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] | ||
| + | |GENE= folA, tmrA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 Escherichia coli]) | ||
| + | }} | ||
| + | |||
| + | '''Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2ANQ is a [ | + | 2ANQ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ANQ OCA]. |
==Reference== | ==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:[http:// | + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/17125251 17125251] |
[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
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[[Category: protein inhibitor complex]] | [[Category: protein inhibitor complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 15:51:45 2008'' |
Revision as of 13:51, 20 March 2008
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| , resolution 2.130Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , and | ||||||
| Gene: | folA, tmrA (Escherichia coli) | ||||||
| Activity: | Dihydrofolate reductase, with EC number 1.5.1.3 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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 Thu Mar 20 15:51:45 2008
