1dhf
From Proteopedia
(New page: 200px<br /> <applet load="1dhf" size="450" color="white" frame="true" align="right" spinBox="true" caption="1dhf, resolution 2.3Å" /> '''CRYSTAL STRUCTURES O...) |
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| - | [[Image:1dhf.gif|left|200px]]<br /> | + | [[Image:1dhf.gif|left|200px]]<br /><applet load="1dhf" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1dhf" size=" | + | |
caption="1dhf, resolution 2.3Å" /> | caption="1dhf, resolution 2.3Å" /> | ||
'''CRYSTAL STRUCTURES OF RECOMBINANT HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH FOLATE AND 5-DEAZOFOLATE'''<br /> | '''CRYSTAL STRUCTURES OF RECOMBINANT HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH FOLATE AND 5-DEAZOFOLATE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The 2.3-A crystal structure of recombinant human dihydrofolate reductase | + | The 2.3-A crystal structure of recombinant human dihydrofolate reductase (EC 1.5.1.3, DHFR) has been solved as a binary complex with folate (a poor substrate at neutral pH) and also as a binary complex with an inhibitor, 5-deazafolate. The inhibitor appears to be protonated at N8 on binding, whereas folate is not. Rotation of the peptide plane joining I7 and V8 from its position in the folate complex permits hydrogen bonding of 5-deazafolate's protonated N8 to the backbone carbonyl of I7, thus contributing to the enzyme's greater affinity for 5-deazafolate than for folate. In this respect it is likely that bound 5-deazafolate furnishes a model for 7,8-dihydrofolate binding and, in addition, resembles the transition state for folate reduction. A hypothetical transition-state model for folate reduction, generated by superposition of the DHFR binary complexes human.5-deazafolate and chicken liver.NADPH, reveals a 1-A overlap of the binding sites for folate's pteridine ring and the dihydronicotinamide ring of NADPH. It is proposed that this binding-site overlap accelerates the reduction of both folate and 7,8-dihydrofolate by simultaneously binding substrate and cofactor with a sub van der Waals separation that is optimal for hydride transfer. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1DHF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FOL as [http://en.wikipedia.org/wiki/ligand ligand]. 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:// | + | 1DHF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=FOL:'>FOL</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=1DHF OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: /II, J | + | [[Category: /II, J F.Davies.]] |
[[Category: Kraut, J.]] | [[Category: Kraut, J.]] | ||
[[Category: FOL]] | [[Category: FOL]] | ||
[[Category: oxido-reductase]] | [[Category: oxido-reductase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:16:37 2008'' |
Revision as of 10:16, 21 February 2008
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CRYSTAL STRUCTURES OF RECOMBINANT HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH FOLATE AND 5-DEAZOFOLATE
Contents |
Overview
The 2.3-A crystal structure of recombinant human dihydrofolate reductase (EC 1.5.1.3, DHFR) has been solved as a binary complex with folate (a poor substrate at neutral pH) and also as a binary complex with an inhibitor, 5-deazafolate. The inhibitor appears to be protonated at N8 on binding, whereas folate is not. Rotation of the peptide plane joining I7 and V8 from its position in the folate complex permits hydrogen bonding of 5-deazafolate's protonated N8 to the backbone carbonyl of I7, thus contributing to the enzyme's greater affinity for 5-deazafolate than for folate. In this respect it is likely that bound 5-deazafolate furnishes a model for 7,8-dihydrofolate binding and, in addition, resembles the transition state for folate reduction. A hypothetical transition-state model for folate reduction, generated by superposition of the DHFR binary complexes human.5-deazafolate and chicken liver.NADPH, reveals a 1-A overlap of the binding sites for folate's pteridine ring and the dihydronicotinamide ring of NADPH. It is proposed that this binding-site overlap accelerates the reduction of both folate and 7,8-dihydrofolate by simultaneously binding substrate and cofactor with a sub van der Waals separation that is optimal for hydride transfer.
Disease
Known disease associated with this structure: Anemia, megaloblastic, due to DHFR deficiency (1) OMIM:[126060]
About this Structure
1DHF is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Full crystallographic information is available from OCA.
Reference
Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate., Davies JF 2nd, Delcamp TJ, Prendergast NJ, Ashford VA, Freisheim JH, Kraut J, Biochemistry. 1990 Oct 9;29(40):9467-79. PMID:2248959
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