1bd4: Difference between revisions

Revision as of 12:54, 21 February 2008

UPRT-URACIL COMPLEX

OverviewOverview

Uracil phosphoribosyltransferase (UPRTase) catalyzes the transfer of a ribosyl phosphate group from alpha-D-5-phosphoribosyl-1-pyrophosphate to the N1 nitrogen of uracil. The UPRTase from the opportunistic pathogen Toxoplasma gondii is a rational target for antiparasitic drug design. To aid in structure-based drug design studies against toxoplasmosis, the crystal structures of the T.gondii apo UPRTase (1.93 A resolution), the UPRTase bound to its substrate, uracil (2.2 A resolution), its product, UMP (2.5 A resolution), and the prodrug, 5-fluorouracil (2.3 A resolution), have been determined. These structures reveal that UPRTase recognizes uracil through polypeptide backbone hydrogen bonds to the uracil exocyclic O2 and endocyclic N3 atoms and a backbone-water-exocyclic O4 oxygen hydrogen bond. This stereochemical arrangement and the architecture of the uracil-binding pocket reveal why cytosine and pyrimidines with exocyclic substituents at ring position 5 larger than fluorine, including thymine, cannot bind to the enzyme. Strikingly, the T. gondii UPRTase contains a 22 residue insertion within the conserved PRTase fold that forms an extended antiparallel beta-arm. Leu92, at the tip of this arm, functions to cap the active site of its dimer mate, thereby inhibiting the escape of the substrate-binding water molecule.

About this StructureAbout this Structure

1BD4 is a Single protein structure of sequence from Toxoplasma gondii with and as ligands. Active as Uracil phosphoribosyltransferase, with EC number 2.4.2.9 Full crystallographic information is available from OCA.

ReferenceReference

Crystal structures of Toxoplasma gondii uracil phosphoribosyltransferase reveal the atomic basis of pyrimidine discrimination and prodrug binding., Schumacher MA, Carter D, Scott DM, Roos DS, Ullman B, Brennan RG, EMBO J. 1998 Jun 15;17(12):3219-32. PMID:9628859

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-[[Image:1bd4.gif|left|200px]]<br /><applet load="1bd4" size="450" color="white" frame="true" align="right" spinBox="true"
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 caption="1bd4, resolution 2.2&Aring;" />
 '''UPRT-URACIL COMPLEX'''<br />
 ==Overview==
-Uracil phosphoribosyltransferase (UPRTase) catalyzes the transfer of a, ribosyl phosphate group from alpha-D-5-phosphoribosyl-1-pyrophosphate to, the N1 nitrogen of uracil. The UPRTase from the opportunistic pathogen, Toxoplasma gondii is a rational target for antiparasitic drug design. To, aid in structure-based drug design studies against toxoplasmosis, the, crystal structures of the T.gondii apo UPRTase (1.93 A resolution), the, UPRTase bound to its substrate, uracil (2.2 A resolution), its product, UMP (2.5 A resolution), and the prodrug, 5-fluorouracil (2.3 A, resolution), have been determined. These structures reveal that UPRTase, recognizes uracil through polypeptide backbone hydrogen bonds to the, uracil exocyclic O2 and endocyclic N3 atoms and a backbone-water-exocyclic, O4 oxygen hydrogen bond. This stereochemical arrangement and the, architecture of the uracil-binding pocket reveal why cytosine and, pyrimidines with exocyclic substituents at ring position 5 larger than, fluorine, including thymine, cannot bind to the enzyme. Strikingly, the T., gondii UPRTase contains a 22 residue insertion within the conserved PRTase, fold that forms an extended antiparallel beta-arm. Leu92, at the tip of, this arm, functions to cap the active site of its dimer mate, thereby, inhibiting the escape of the substrate-binding water molecule.
+Uracil phosphoribosyltransferase (UPRTase) catalyzes the transfer of a ribosyl phosphate group from alpha-D-5-phosphoribosyl-1-pyrophosphate to the N1 nitrogen of uracil. The UPRTase from the opportunistic pathogen Toxoplasma gondii is a rational target for antiparasitic drug design. To aid in structure-based drug design studies against toxoplasmosis, the crystal structures of the T.gondii apo UPRTase (1.93 A resolution), the UPRTase bound to its substrate, uracil (2.2 A resolution), its product, UMP (2.5 A resolution), and the prodrug, 5-fluorouracil (2.3 A resolution), have been determined. These structures reveal that UPRTase recognizes uracil through polypeptide backbone hydrogen bonds to the uracil exocyclic O2 and endocyclic N3 atoms and a backbone-water-exocyclic O4 oxygen hydrogen bond. This stereochemical arrangement and the architecture of the uracil-binding pocket reveal why cytosine and pyrimidines with exocyclic substituents at ring position 5 larger than fluorine, including thymine, cannot bind to the enzyme. Strikingly, the T. gondii UPRTase contains a 22 residue insertion within the conserved PRTase fold that forms an extended antiparallel beta-arm. Leu92, at the tip of this arm, functions to cap the active site of its dimer mate, thereby inhibiting the escape of the substrate-binding water molecule.
 ==About this Structure==
-BD4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii] with PO4 and URA as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Uracil_phosphoribosyltransferase Uracil phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.9 2.4.2.9] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1BD4 OCA].
+BD4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii] with <scene name='pdbligand=PO4:'>PO4</scene> and <scene name='pdbligand=URA:'>URA</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Uracil_phosphoribosyltransferase Uracil phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.9 2.4.2.9] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BD4 OCA].
 ==Reference==
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 [[Category: Toxoplasma gondii]]
 [[Category: Uracil phosphoribosyltransferase]]
-[[Category: Brennan, R.G.]]
+[[Category: Brennan, R G.]]
 [[Category: Carter, D.]]
 [[Category: Roos, D.]]
-[[Category: Schumacher, M.A.]]
+[[Category: Schumacher, M A.]]
 [[Category: Scott, D.]]
 [[Category: Ullman, B.]]
@@ Line 28: / Line 28: @@
 [[Category: uracil]]
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