1d3h: Difference between revisions

Revision as of 13:12, 21 February 2008

HUMAN DIHYDROOROTATE DEHYDROGENASE COMPLEXED WITH ANTIPROLIFERATIVE AGENT A771726

OverviewOverview

BACKGROUND: Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth committed step in the de novo biosynthesis of pyrimidines. As rapidly proliferating human T cells have an exceptional requirement for de novo pyrimidine biosynthesis, small molecule DHODH inhibitors constitute an attractive therapeutic approach to autoimmune diseases, immunosuppression, and cancer. Neither the structure of human DHODH nor any member of its family was known. RESULTS: The high-resolution crystal structures of human DHODH in complex with two different inhibitors have been solved. The initial set of phases was obtained using multiwavelength anomalous diffraction phasing with selenomethionine-containing DHODH. The structures have been refined to crystallographic R factors of 16.8% and 16.2% at resolutions of 1. 6 A and 1.8 A for inhibitors related to brequinar and leflunomide, respectively. CONCLUSIONS: Human DHODH has two domains: an alpha/beta-barrel domain containing the active site and an alpha-helical domain that forms the opening of a tunnel leading to the active site. Both inhibitors share a common binding site in this tunnel, and differences in the binding region govern drug sensitivity or resistance. The active site of human DHODH is generally similar to that of the previously reported bacterial active site. The greatest differences are that the catalytic base removing the proton from dihydroorotate is a serine rather than a cysteine, and that packing of the flavin mononucleotide in its binding site is tighter.

About this StructureAbout this Structure

1D3H is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Active as Dihydroorotate oxidase, with EC number 1.3.3.1 Full crystallographic information is available from OCA.

ReferenceReference

Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents., Liu S, Neidhardt EA, Grossman TH, Ocain T, Clardy J, Structure. 2000 Jan 15;8(1):25-33. PMID:10673429

Page seeded by OCA on Thu Feb 21 12:12:39 2008

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OCA

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-[[Image:1d3h.gif|left|200px]]<br />
+[[Image:1d3h.gif|left|200px]]<br /><applet load="1d3h" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1d3h" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1d3h, resolution 1.80&Aring;" />
 '''HUMAN DIHYDROOROTATE DEHYDROGENASE COMPLEXED WITH ANTIPROLIFERATIVE AGENT A771726'''<br />
 ==Overview==
-BACKGROUND: Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth, committed step in the de novo biosynthesis of pyrimidines. As rapidly, proliferating human T cells have an exceptional requirement for de novo, pyrimidine biosynthesis, small molecule DHODH inhibitors constitute an, attractive therapeutic approach to autoimmune diseases, immunosuppression, and cancer. Neither the structure of human DHODH nor any member of its, family was known. RESULTS: The high-resolution crystal structures of human, DHODH in complex with two different inhibitors have been solved. The, initial set of phases was obtained using multiwavelength anomalous, diffraction phasing with selenomethionine-containing DHODH. The structures, have been refined to crystallographic R factors of 16.8% and 16.2% at, resolutions of 1. 6 A and 1.8 A for inhibitors related to brequinar and, leflunomide, respectively. CONCLUSIONS: Human DHODH has two domains: an, alpha/beta-barrel domain containing the active site and an alpha-helical, domain that forms the opening of a tunnel leading to the active site. Both, inhibitors share a common binding site in this tunnel, and differences in, the binding region govern drug sensitivity or resistance. The active site, of human DHODH is generally similar to that of the previously reported, bacterial active site. The greatest differences are that the catalytic, base removing the proton from dihydroorotate is a serine rather than a, cysteine, and that packing of the flavin mononucleotide in its binding, site is tighter.
+BACKGROUND: Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth committed step in the de novo biosynthesis of pyrimidines. As rapidly proliferating human T cells have an exceptional requirement for de novo pyrimidine biosynthesis, small molecule DHODH inhibitors constitute an attractive therapeutic approach to autoimmune diseases, immunosuppression, and cancer. Neither the structure of human DHODH nor any member of its family was known. RESULTS: The high-resolution crystal structures of human DHODH in complex with two different inhibitors have been solved. The initial set of phases was obtained using multiwavelength anomalous diffraction phasing with selenomethionine-containing DHODH. The structures have been refined to crystallographic R factors of 16.8% and 16.2% at resolutions of 1. 6 A and 1.8 A for inhibitors related to brequinar and leflunomide, respectively. CONCLUSIONS: Human DHODH has two domains: an alpha/beta-barrel domain containing the active site and an alpha-helical domain that forms the opening of a tunnel leading to the active site. Both inhibitors share a common binding site in this tunnel, and differences in the binding region govern drug sensitivity or resistance. The active site of human DHODH is generally similar to that of the previously reported bacterial active site. The greatest differences are that the catalytic base removing the proton from dihydroorotate is a serine rather than a cysteine, and that packing of the flavin mononucleotide in its binding site is tighter.
 ==About this Structure==
-D3H 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, ACT, A26, FMN and ORO as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydroorotate_oxidase Dihydroorotate oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.3.1 1.3.3.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1D3H OCA].
+D3H 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=ACT:'>ACT</scene>, <scene name='pdbligand=A26:'>A26</scene>, <scene name='pdbligand=FMN:'>FMN</scene> and <scene name='pdbligand=ORO:'>ORO</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydroorotate_oxidase Dihydroorotate oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.3.1 1.3.3.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D3H OCA].
 ==Reference==
@@ Line 16: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Clardy, J.]]
-[[Category: Grossman, T.H.]]
+[[Category: Grossman, T H.]]
 [[Category: Liu, S.]]
-[[Category: Neidhardt, E.A.]]
+[[Category: Neidhardt, E A.]]
 [[Category: Ocain, T.]]
 [[Category: A26]]
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 [[Category: oxidoreductase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:28:15 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:12:39 2008''