1dyr: Difference between revisions

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THE STRUCTURE OF PNEUMOCYSTIS CARINII DIHYDROFOLATE REDUCTASE TO 1.9 ANGSTROMS RESOLUTION

OverviewOverview

BACKGROUND: The fungal pathogen Pneumocystis carinii causes a pneumonia which is an opportunistic infection of AIDS patients. Current therapy includes the dihydrofolate reductase (DHFR) inhibitor trimethoprim which is selective but only a relatively weak inhibitor of the enzyme for P. carinii. Determination of the three-dimensional structure of the enzyme should form the basis for design of more potent and selective therapeutic agents for treatment of the disease. RESULTS: The structure of P. carinii DHFR in complex with reduced nicotinamide adenine dinucleotide phosphate and trimethoprim has accordingly been solved by X-ray crystallography. The structure of the ternary complex has been refined at 1.86 A resolution (R = 0.181). A similar ternary complex with piritrexim (which is a tighter binding, but less selective inhibitor) has also been solved, as has the binary complex holoenzyme, both at 2.5 A resolution. CONCLUSIONS: These structures show how two drugs interact with a fungal DHFR. A comparison of the three-dimensional structure of this relatively large DHFR with bacterial or mammalian enzyme-inhibitor complexes determined previously highlights some additional secondary structure elements in this particular enzyme species. These comparisons provide further insight into the principles governing DHFR-inhibitor interaction, in which the volume of the active site appears to determine the strength of inhibitor binding.

About this StructureAbout this Structure

1DYR is a Single protein structure of sequence from Pneumocystis carinii with and as ligands. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Full crystallographic information is available from OCA.

ReferenceReference

The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 A resolution., Champness JN, Achari A, Ballantine SP, Bryant PK, Delves CJ, Stammers DK, Structure. 1994 Oct 15;2(10):915-24. PMID:7866743

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-[[Image:1dyr.gif|left|200px]]<br /><applet load="1dyr" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1dyr.gif|left|200px]]<br /><applet load="1dyr" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1dyr, resolution 1.86&Aring;" />
 '''THE STRUCTURE OF PNEUMOCYSTIS CARINII DIHYDROFOLATE REDUCTASE TO 1.9 ANGSTROMS RESOLUTION'''<br />
 ==Overview==
-BACKGROUND: The fungal pathogen Pneumocystis carinii causes a pneumonia, which is an opportunistic infection of AIDS patients. Current therapy, includes the dihydrofolate reductase (DHFR) inhibitor trimethoprim which, is selective but only a relatively weak inhibitor of the enzyme for P., carinii. Determination of the three-dimensional structure of the enzyme, should form the basis for design of more potent and selective therapeutic, agents for treatment of the disease. RESULTS: The structure of P. carinii, DHFR in complex with reduced nicotinamide adenine dinucleotide phosphate, and trimethoprim has accordingly been solved by X-ray crystallography. The, structure of the ternary complex has been refined at 1.86 A resolution (R, = 0.181). A similar ternary complex with piritrexim (which is a tighter, binding, but less selective inhibitor) has also been solved, as has the, binary complex holoenzyme, both at 2.5 A resolution. CONCLUSIONS: These, structures show how two drugs interact with a fungal DHFR. A comparison of, the three-dimensional structure of this relatively large DHFR with, bacterial or mammalian enzyme-inhibitor complexes determined previously, highlights some additional secondary structure elements in this particular, enzyme species. These comparisons provide further insight into the, principles governing DHFR-inhibitor interaction, in which the volume of, the active site appears to determine the strength of inhibitor binding.
+BACKGROUND: The fungal pathogen Pneumocystis carinii causes a pneumonia which is an opportunistic infection of AIDS patients. Current therapy includes the dihydrofolate reductase (DHFR) inhibitor trimethoprim which is selective but only a relatively weak inhibitor of the enzyme for P. carinii. Determination of the three-dimensional structure of the enzyme should form the basis for design of more potent and selective therapeutic agents for treatment of the disease. RESULTS: The structure of P. carinii DHFR in complex with reduced nicotinamide adenine dinucleotide phosphate and trimethoprim has accordingly been solved by X-ray crystallography. The structure of the ternary complex has been refined at 1.86 A resolution (R = 0.181). A similar ternary complex with piritrexim (which is a tighter binding, but less selective inhibitor) has also been solved, as has the binary complex holoenzyme, both at 2.5 A resolution. CONCLUSIONS: These structures show how two drugs interact with a fungal DHFR. A comparison of the three-dimensional structure of this relatively large DHFR with bacterial or mammalian enzyme-inhibitor complexes determined previously highlights some additional secondary structure elements in this particular enzyme species. These comparisons provide further insight into the principles governing DHFR-inhibitor interaction, in which the volume of the active site appears to determine the strength of inhibitor binding.
 ==About this Structure==
-DYR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Pneumocystis_carinii Pneumocystis carinii] with NDP and TOP 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1DYR OCA].
+DYR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Pneumocystis_carinii Pneumocystis carinii] with <scene name='pdbligand=NDP:'>NDP</scene> and <scene name='pdbligand=TOP:'>TOP</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=1DYR OCA].
 ==Reference==
@@ Line 15: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Achari, A.]]
-[[Category: Ballantine, S.P.]]
+[[Category: Ballantine, S P.]]
-[[Category: Bryant, P.K.]]
+[[Category: Bryant, P K.]]
-[[Category: Champness, J.N.]]
+[[Category: Champness, J N.]]
-[[Category: Delves, C.J.]]
+[[Category: Delves, C J.]]
-[[Category: Stammers, D.K.]]
+[[Category: Stammers, D K.]]
 [[Category: NDP]]
 [[Category: TOP]]
 [[Category: oxido-reductase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 13:41:19 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:21:55 2008''