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The Crystal Structure of a Novel, Latent Dihydroorotase from Aquifex Aeolicus at 1.7 A Resolution

OverviewOverview

Dihydroorotases (EC 3.5.2.3) catalyze the reversible cyclization of carbamoyl aspartate to form dihydroorotate in de novo pyrimidine biosynthesis. The X-ray structures of Aquifex aeolicus dihydroorotase in two space groups, C222(1) and C2, were determined at a resolution of 1.7A. These are the first structures of a type I dihydroorotase, a class of molecules that includes the dihydroorotase domain of mammalian CAD. The type I enzymes are more ancient and larger, at 45 kDa, than the type II enzymes exemplified by the 38 kDa Escherichia coli dihydroorotase. Both dihydroorotases are members of the metallo-dependent hydrolase superfamily, whose members have a distorted "TIM barrel" domain containing the active site. However, A.aeolicus dihydroorotase has a second, composite domain, which the E.coli enzyme lacks and has only one of the two zinc atoms present in the E.coli enzyme. A.aeolicus dihydroorotase is unique in exhibiting significant activity only when complexed with aspartate transcarbamoylase, whereas the E.coli dihydroorotase and the CAD dihydroorotase domain are active as free proteins. The latency of A.aeolicus dihydroorotase can be related to two differences between its structure and that of E.coli dihydroorotase: (1) the monoclinic structure has a novel cysteine ligand to the zinc that blocks the active site and possibly functions as a "cysteine switch"; and (2) active site residues that bind the substrate in E.coli dihydroorotase are located in disordered loops in both crystal structures of A.aeolicus dihydroorotase and may function as a disorder-to-order "entropy switch".

About this StructureAbout this Structure

1XRT is a Single protein structure of sequence from Aquifex aeolicus with as ligand. Active as Dihydroorotase, with EC number 3.5.2.3 Full crystallographic information is available from OCA.

ReferenceReference

The crystal structure of a novel, latent dihydroorotase from Aquifex aeolicus at 1.7A resolution., Martin PD, Purcarea C, Zhang P, Vaishnav A, Sadecki S, Guy-Evans HI, Evans DR, Edwards BF, J Mol Biol. 2005 May 6;348(3):535-47. PMID:15826652

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-[[Image:1xrt.gif|left|200px]]<br /><applet load="1xrt" size="450" color="white" frame="true" align="right" spinBox="true"
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 caption="1xrt, resolution 1.609&Aring;" />
 '''The Crystal Structure of a Novel, Latent Dihydroorotase from Aquifex Aeolicus at 1.7 A Resolution'''<br />
 ==Overview==
-Dihydroorotases (EC 3.5.2.3) catalyze the reversible cyclization of, carbamoyl aspartate to form dihydroorotate in de novo pyrimidine, biosynthesis. The X-ray structures of Aquifex aeolicus dihydroorotase in, two space groups, C222(1) and C2, were determined at a resolution of 1.7A., These are the first structures of a type I dihydroorotase, a class of, molecules that includes the dihydroorotase domain of mammalian CAD. The, type I enzymes are more ancient and larger, at 45 kDa, than the type II, enzymes exemplified by the 38 kDa Escherichia coli dihydroorotase. Both, dihydroorotases are members of the metallo-dependent hydrolase, superfamily, whose members have a distorted "TIM barrel" domain containing, the active site. However, A.aeolicus dihydroorotase has a second, composite domain, which the E.coli enzyme lacks and has only one of the, two zinc atoms present in the E.coli enzyme. A.aeolicus dihydroorotase is, unique in exhibiting significant activity only when complexed with, aspartate transcarbamoylase, whereas the E.coli dihydroorotase and the CAD, dihydroorotase domain are active as free proteins. The latency of, A.aeolicus dihydroorotase can be related to two differences between its, structure and that of E.coli dihydroorotase: (1) the monoclinic structure, has a novel cysteine ligand to the zinc that blocks the active site and, possibly functions as a "cysteine switch"; and (2) active site residues, that bind the substrate in E.coli dihydroorotase are located in disordered, loops in both crystal structures of A.aeolicus dihydroorotase and may, function as a disorder-to-order "entropy switch".
+Dihydroorotases (EC 3.5.2.3) catalyze the reversible cyclization of carbamoyl aspartate to form dihydroorotate in de novo pyrimidine biosynthesis. The X-ray structures of Aquifex aeolicus dihydroorotase in two space groups, C222(1) and C2, were determined at a resolution of 1.7A. These are the first structures of a type I dihydroorotase, a class of molecules that includes the dihydroorotase domain of mammalian CAD. The type I enzymes are more ancient and larger, at 45 kDa, than the type II enzymes exemplified by the 38 kDa Escherichia coli dihydroorotase. Both dihydroorotases are members of the metallo-dependent hydrolase superfamily, whose members have a distorted "TIM barrel" domain containing the active site. However, A.aeolicus dihydroorotase has a second, composite domain, which the E.coli enzyme lacks and has only one of the two zinc atoms present in the E.coli enzyme. A.aeolicus dihydroorotase is unique in exhibiting significant activity only when complexed with aspartate transcarbamoylase, whereas the E.coli dihydroorotase and the CAD dihydroorotase domain are active as free proteins. The latency of A.aeolicus dihydroorotase can be related to two differences between its structure and that of E.coli dihydroorotase: (1) the monoclinic structure has a novel cysteine ligand to the zinc that blocks the active site and possibly functions as a "cysteine switch"; and (2) active site residues that bind the substrate in E.coli dihydroorotase are located in disordered loops in both crystal structures of A.aeolicus dihydroorotase and may function as a disorder-to-order "entropy switch".
 ==About this Structure==
-XRT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Aquifex_aeolicus Aquifex aeolicus] with ZN as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Dihydroorotase Dihydroorotase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.3 3.5.2.3] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1XRT OCA].
+XRT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Aquifex_aeolicus Aquifex aeolicus] with <scene name='pdbligand=ZN:'>ZN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Dihydroorotase Dihydroorotase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.3 3.5.2.3] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XRT OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Dihydroorotase]]
 [[Category: Single protein]]
-[[Category: Edwards, B.F.]]
+[[Category: Edwards, B F.]]
-[[Category: Evans, D.R.]]
+[[Category: Evans, D R.]]
-[[Category: Guy-Evans, H.I.]]
+[[Category: Guy-Evans, H I.]]
-[[Category: Martin, P.D.]]
+[[Category: Martin, P D.]]
 [[Category: Purcarea, C.]]
 [[Category: Sadecki, S.]]
@@ Line 29: / Line 29: @@
 [[Category: zinc]]
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