1pd8
From Proteopedia
(New page: 200px<br /> <applet load="1pd8" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pd8, resolution 2.1Å" /> '''Analysis of Three Cr...) |
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caption="1pd8, resolution 2.1Å" /> | caption="1pd8, resolution 2.1Å" /> | ||
'''Analysis of Three Crystal Structure Determinations of a 5-Methyl-6-N-Methylanilino Pyridopyrimidine Antifolate Complex with Human Dihydrofolate Reductase'''<br /> | '''Analysis of Three Crystal Structure Determinations of a 5-Methyl-6-N-Methylanilino Pyridopyrimidine Antifolate Complex with Human Dihydrofolate Reductase'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1PD8 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 NDP and CO4 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:// | + | 1PD8 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=NDP:'>NDP</scene> and <scene name='pdbligand=CO4:'>CO4</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=1PD8 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: human dihydrofolate reductase inhibitor complex]] | [[Category: human dihydrofolate reductase inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:39:44 2008'' |
Revision as of 14:39, 15 February 2008
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Analysis of Three Crystal Structure Determinations of a 5-Methyl-6-N-Methylanilino Pyridopyrimidine Antifolate Complex with Human Dihydrofolate Reductase
Contents |
Overview
Structural data are reported for the first example of the potent, antifolate inhibitor, 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxy-N-methylanilino)methyl]pyrido, [2,3-d]pyrimidine (1) in complex with human dihydrofolate reductase, (hDHFR) and NADPH. Small differences in crystallization conditions, resulted in the growth of two different forms of a binary complex. The, structure determination of an additional crystal of a ternary complex of, hDHFR with NADPH and (1) grown under similar conditions is also reported., Diffraction data were collected to 2.1 A resolution for an R3 lattice from, a hDHFR ternary complex with NADPH and (1) and to 2.2 A resolution from a, binary complex. Data were also collected to 2.1 A resolution from a binary, complex with hDHFR and (1) in the first example of a tetragonal P4(3)2(1)2, lattice. Comparison of the intermolecular contacts among these structures, reveals differences in the backbone conformation (1.9-3.2 A) for flexible, loop regions (residues 40-46, 77-83 and 103-107) that reflect differences, in the packing environment between the rhombohedral and tetragonal space, groups. Analysis of the packing environments shows that the tetragonal, lattice is more tightly packed, as reflected in its smaller V(M) value and, lower solvent content. The conformation of the inhibitor (1) is similar in, all structures and is also similar to that observed for TMQ, the parent, quinazoline compound. The activity profile for this series of 5-deaza, N-substituted non-classical trimethoxybenzyl antifolates shows that the, N10-CH(3) substituted (1) has the greatest potency and selectivity for, Toxoplasma gondii DHFR (tgDHFR) compared with its N-H or N-CHO analogs., Models of the tgDHFR active site indicate preferential contacts with (1), that are not present in either the human or Pneumocystis carinii DHFR, structures. Differences in the acidic residue (Glu30 versus Asp for, tgDHFR) affect the precise positioning of the diaminopyridopyrimidine, ring, while changes in other residues, particularly at positions 60 and 64, (Leu versus Met and Asn versus Phe), involve interactions with the, trimethoxybenzyl substituents.
Disease
Known disease associated with this structure: Anemia, megaloblastic, due to DHFR deficiency (1) OMIM:[126060]
About this Structure
1PD8 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
Analysis of three crystal structure determinations of a 5-methyl-6-N-methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase., Cody V, Luft JR, Pangborn W, Gangjee A, Acta Crystallogr D Biol Crystallogr. 2003 Sep;59(Pt 9):1603-9. Epub 2003, Aug 19. PMID:12925791
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