1kmv
From Proteopedia
(New page: 200px<br /> <applet load="1kmv" size="450" color="white" frame="true" align="right" spinBox="true" caption="1kmv, resolution 1.05Å" /> '''HUMAN DIHYDROFOLATE...) |
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| - | [[Image:1kmv.gif|left|200px]]<br /> | + | [[Image:1kmv.gif|left|200px]]<br /><applet load="1kmv" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1kmv, resolution 1.05Å" /> | caption="1kmv, resolution 1.05Å" /> | ||
'''HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND (Z)-6-(2-[2,5-DIMETHOXYPHENYL]ETHEN-1-YL)-2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINE (SRI-9662), A LIPOPHILIC ANTIFOLATE'''<br /> | '''HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND (Z)-6-(2-[2,5-DIMETHOXYPHENYL]ETHEN-1-YL)-2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINE (SRI-9662), A LIPOPHILIC ANTIFOLATE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The crystal structures of two human dihydrofolate reductase (hDHFR) | + | The crystal structures of two human dihydrofolate reductase (hDHFR) ternary complexes, each with bound NADPH cofactor and a lipophilic antifolate inhibitor, have been determined at atomic resolution. The potent inhibitors 6-([5-quinolylamino]methyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (SRI-9439) and (Z)-6-(2-[2,5-dimethoxyphenyl]ethen-1-yl)-2,4-diamino-5-methylpyrido[2,3-d ]pyrimidine (SRI-9662) were developed at Southern Research Institute against Toxoplasma gondii DHFR-thymidylate synthase. The 5-deazapteridine ring of each inhibitor adopts an unusual puckered conformation that enables the formation of identical contacts in the active site. Conversely, the quinoline and dimethoxybenzene moieties exhibit distinct binding characteristics that account for the differences in inhibitory activity. In both structures, a salt-bridge is formed between Arg70 in the active site and Glu44 from a symmetry-related molecule in the crystal lattice that mimics the binding of methotrexate to DHFR. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1KMV 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 SO4, LII, NDP and DMS 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:// | + | 1KMV 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=SO4:'>SO4</scene>, <scene name='pdbligand=LII:'>LII</scene>, <scene name='pdbligand=NDP:'>NDP</scene> and <scene name='pdbligand=DMS:'>DMS</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=1KMV OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Borhani, D | + | [[Category: Borhani, D W.]] |
[[Category: Heroux, A.]] | [[Category: Heroux, A.]] | ||
| - | [[Category: Johnson, C | + | [[Category: Johnson, C A.]] |
| - | [[Category: Klon, A | + | [[Category: Klon, A E.]] |
[[Category: Pathak, V.]] | [[Category: Pathak, V.]] | ||
| - | [[Category: Piper, J | + | [[Category: Piper, J R.]] |
| - | [[Category: Ross, L | + | [[Category: Ross, L J.]] |
[[Category: DMS]] | [[Category: DMS]] | ||
[[Category: LII]] | [[Category: LII]] | ||
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[[Category: reductase]] | [[Category: reductase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:35:51 2008'' |
Revision as of 11:35, 21 February 2008
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HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND (Z)-6-(2-[2,5-DIMETHOXYPHENYL]ETHEN-1-YL)-2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINE (SRI-9662), A LIPOPHILIC ANTIFOLATE
Contents |
Overview
The crystal structures of two human dihydrofolate reductase (hDHFR) ternary complexes, each with bound NADPH cofactor and a lipophilic antifolate inhibitor, have been determined at atomic resolution. The potent inhibitors 6-([5-quinolylamino]methyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (SRI-9439) and (Z)-6-(2-[2,5-dimethoxyphenyl]ethen-1-yl)-2,4-diamino-5-methylpyrido[2,3-d ]pyrimidine (SRI-9662) were developed at Southern Research Institute against Toxoplasma gondii DHFR-thymidylate synthase. The 5-deazapteridine ring of each inhibitor adopts an unusual puckered conformation that enables the formation of identical contacts in the active site. Conversely, the quinoline and dimethoxybenzene moieties exhibit distinct binding characteristics that account for the differences in inhibitory activity. In both structures, a salt-bridge is formed between Arg70 in the active site and Glu44 from a symmetry-related molecule in the crystal lattice that mimics the binding of methotrexate to DHFR.
Disease
Known disease associated with this structure: Anemia, megaloblastic, due to DHFR deficiency (1) OMIM:[126060]
About this Structure
1KMV is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Full crystallographic information is available from OCA.
Reference
Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution., Klon AE, Heroux A, Ross LJ, Pathak V, Johnson CA, Piper JR, Borhani DW, J Mol Biol. 2002 Jul 12;320(3):677-93. PMID:12096917
Page seeded by OCA on Thu Feb 21 13:35:51 2008
Categories: Dihydrofolate reductase | Homo sapiens | Single protein | Borhani, D W. | Heroux, A. | Johnson, C A. | Klon, A E. | Pathak, V. | Piper, J R. | Ross, L J. | DMS | LII | NDP | SO4 | Antiparasitic drugs | Lipophilic antifolates | Oxidoreductase | Reductase
