1s3y
From Proteopedia
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| - | [[Image:1s3y.jpg|left|200px]] | + | [[Image:1s3y.jpg|left|200px]] |
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| - | '''Structure Determination of Tetrahydroquinazoline Antifolates in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry''' | + | {{Structure |
| + | |PDB= 1s3y |SIZE=350|CAPTION= <scene name='initialview01'>1s3y</scene>, resolution 2.25Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene> and <scene name='pdbligand=TQT:6-(OCTAHYDRO-1H-INDOL-1-YLMETHYL)DECAHYDROQUINAZOLINE-2,4-DIAMINE'>TQT</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= | ||
| + | }} | ||
| + | |||
| + | '''Structure Determination of Tetrahydroquinazoline Antifolates in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry''' | ||
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==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1S3Y is a [ | + | 1S3Y is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Pneumocystis_carinii Pneumocystis carinii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1S3Y OCA]. |
==Reference== | ==Reference== | ||
| - | Structure determination of tetrahydroquinazoline antifolates in complex with human and Pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry., Cody V, Luft JR, Pangborn W, Gangjee A, Queener SF, Acta Crystallogr D Biol Crystallogr. 2004 Apr;60(Pt 4):646-55. Epub 2004, Mar 23. PMID:[http:// | + | Structure determination of tetrahydroquinazoline antifolates in complex with human and Pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry., Cody V, Luft JR, Pangborn W, Gangjee A, Queener SF, Acta Crystallogr D Biol Crystallogr. 2004 Apr;60(Pt 4):646-55. Epub 2004, Mar 23. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15039552 15039552] |
[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
[[Category: Pneumocystis carinii]] | [[Category: Pneumocystis carinii]] | ||
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[[Category: NAP]] | [[Category: NAP]] | ||
[[Category: TQT]] | [[Category: TQT]] | ||
| - | [[Category: | + | [[Category: inhibitor]] |
[[Category: pneumocystis carinii dihydrofolate reductase]] | [[Category: pneumocystis carinii dihydrofolate reductase]] | ||
[[Category: stereochemistry]] | [[Category: stereochemistry]] | ||
| - | ''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 14:00:09 2008'' |
Revision as of 12:00, 20 March 2008
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| , resolution 2.25Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Activity: | Dihydrofolate reductase, with EC number 1.5.1.3 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure Determination of Tetrahydroquinazoline Antifolates in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry
Overview
Structural data are reported for the first examples of the tetrahydroquinazoline antifolate (6R,6S)-2,4-diamino-6-(1-indolinomethyl)-5,6,7,8-tetrahydroquinazoline (1) and its trimethoxy analogue (6R,6S)-2,4-diamino-6-(3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydroquinaz oline (2) as inhibitor complexes with dihydrofolate reductase (DHFR) from human (hDHFR) and Pneumocystis carinii (pcDHFR) sources. The indoline analogue (1) was crystallized as ternary complexes with NADPH and hDHFR (1.9 A resolution) and pcDHFR (2.3 A resolution), while the trimethoxy quinazoline analogue (2) was crystallized as a binary complex with hDHFR in two polymorphic rhombohedral R3 lattices: R3(1) to 1.8 A resolution and R3(2) to 2.0 A resolution. Structural analysis of these potent and selective DHFR-inhibitor complexes revealed preferential binding of the 6S-equatorial isomer in each structure. This configuration is similar to that of the natural tetrahydrofolate substrate; that is, 6S. These data also show that in both the hDHFR and pcDHFR ternary complexes with (1) the indoline ring is partially disordered, with two static conformations that differ between structures. These conformers also differ from that observed for the trimethoxybenzyl ring of tetrahydroquinazoline (2). There is also a correlation between the disorder of the flexible loop 23 and the disorder of the cofactor nicotinamide ribose ring in the pcDHFR-NADPH-(1) ternary complex. Comparison of the Toxoplasma gondii DHFR (tgDHFR) sequence with those of other DHFRs provides insight into the role of sequence and conformation in inhibitor-binding preferences which may aid in the design of novel antifolates with specific DHFR selectivity.
About this Structure
1S3Y is a Single protein structure of sequence from Pneumocystis carinii. Full crystallographic information is available from OCA.
Reference
Structure determination of tetrahydroquinazoline antifolates in complex with human and Pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry., Cody V, Luft JR, Pangborn W, Gangjee A, Queener SF, Acta Crystallogr D Biol Crystallogr. 2004 Apr;60(Pt 4):646-55. Epub 2004, Mar 23. PMID:15039552
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