1ohj
From Proteopedia
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| - | [[Image:1ohj.gif|left|200px]] | + | [[Image:1ohj.gif|left|200px]] |
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| - | '''HUMAN DIHYDROFOLATE REDUCTASE, MONOCLINIC (P21) CRYSTAL FORM''' | + | {{Structure |
| + | |PDB= 1ohj |SIZE=350|CAPTION= <scene name='initialview01'>1ohj</scene>, resolution 2.50Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene> and <scene name='pdbligand=COP:N-(4-CARBOXY-4-{4-[(2,4-DIAMINO-PTERIDIN-6-YLMETHYL)-AMINO]-BENZOYLAMINO}-BUTYL)-PHTHALAMIC ACID'>COP</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= POTENTIAL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | }} | ||
| + | |||
| + | '''HUMAN DIHYDROFOLATE REDUCTASE, MONOCLINIC (P21) CRYSTAL FORM''' | ||
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==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1OHJ is a [ | + | 1OHJ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OHJ OCA]. |
==Reference== | ==Reference== | ||
| - | Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523., Cody V, Galitsky N, Luft JR, Pangborn W, Rosowsky A, Blakley RL, Biochemistry. 1997 Nov 11;36(45):13897-903. PMID:[http:// | + | Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523., Cody V, Galitsky N, Luft JR, Pangborn W, Rosowsky A, Blakley RL, Biochemistry. 1997 Nov 11;36(45):13897-903. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9374868 9374868] |
[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
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[[Category: oxidoreductase]] | [[Category: oxidoreductase]] | ||
| - | ''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 13:10:58 2008'' |
Revision as of 11:11, 20 March 2008
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| , resolution 2.50Å | |||||||
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| Ligands: | and | ||||||
| Gene: | POTENTIAL (Homo sapiens) | ||||||
| Activity: | Dihydrofolate reductase, with EC number 1.5.1.3 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
HUMAN DIHYDROFOLATE REDUCTASE, MONOCLINIC (P21) CRYSTAL FORM
Contents |
Overview
Structural data for two independent crystal forms (monoclinic, C2, and orthorhombic, P2(1)2(1)2(1)) of the ternary complex of the potent antitumor agent PT523 [N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine], reduced nicotinamide adenine dinucleotide phosphate (NADPH), and recombinant human dihydrofolate reductase (hDHFR) reveals multiple binding orientations for the hemiphthaloyl group of the inhibitor. Analysis of these data shows that PT523 binds with its pteridine ring in the same orientation observed for methotrexate (MTX) analogues. However, in each structure, the hemiphthaloyl ring occupies three alternate conformations. In the C2 lattice, the phthaloyl moiety binds in two extended conformations, A and C, with each conformer having a 180 degrees flip of the o-carboxylate group, and a third, lower occupancy conformer B, with the phthaloyl group folded within contact of the active-site pocket. In the orthorhombic lattice, PT523 also has three conformers for the phthaloyl group; however, these differ from those observed in the monoclinic lattice. Two major conformers, A and C, are displaced on either side of the extended position observed in the C2 lattice, one near the folded B conformer of the C2 lattice and the other extended. These conformers form tighter intermolecular contacts than those in the C2 lattice. Conformer B is folded back away from the active site in a unique position. There are also significant differences in the conformation of the adenine-ribose moiety of NADPH in both complexes that differ from that observed for other inhibitor-NADPH-hDHFR ternary complexes. These data suggest that the added intermolecular contacts made by the hemiphaloyl group of PT523 contribute to its tighter binding to hDHFR than MTX, which does not extend as far from the active site and cannot make these contacts. These crystallographic observations of multiple conformations for the hemiphthaloyl group are in general agreement with solution NMR data for the binding of PT523 to hDHFR [Johnson et al. (1997) Biochemistry 36, 4399-4411], which show that the hemiphthaloyl group may adopt more than one conformation. However, the crystallographic data reveal more discretely occupied positions than can be interpreted from the solution data. These results suggest that crystal packing interactions may influence their stability.
Disease
Known disease associated with this structure: Anemia, megaloblastic, due to DHFR deficiency (1) OMIM:[126060]
About this Structure
1OHJ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523., Cody V, Galitsky N, Luft JR, Pangborn W, Rosowsky A, Blakley RL, Biochemistry. 1997 Nov 11;36(45):13897-903. PMID:9374868
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