1upf: Difference between revisions

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[[Image:1upf.jpg|left|200px]]<br /><applet load="1upf" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

[[Image:1upf.jpg|left|200px]]<br /><applet load="1upf" size="350" color="white" frame="true" align="right" spinBox="true"

caption="1upf, resolution 2.3Å" />

'''STRUCTURE OF THE URACIL PHOSPHORIBOSYLTRANSFERASE, MUTANT C128V BOUND TO THE DRUG 5-FLUOROURACIL'''<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==

1UPF 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 SO4 and URF 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=1UPF OCA].

1UPF 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=SO4:'>SO4</scene> and <scene name='pdbligand=URF:'>URF</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=1UPF OCA].

==Reference==

Line 14:

[[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 26:

[[Category: transferase]]

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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:26:59 2008''

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@@ Line 1: / Line 1: @@
-[[Image:1upf.jpg|left|200px]]<br /><applet load="1upf" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1upf.jpg|left|200px]]<br /><applet load="1upf" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1upf, resolution 2.3&Aring;" />
 '''STRUCTURE OF THE URACIL PHOSPHORIBOSYLTRANSFERASE, MUTANT C128V BOUND TO THE DRUG 5-FLUOROURACIL'''<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==
-UPF 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 SO4 and URF 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=1UPF OCA].
+UPF 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=SO4:'>SO4</scene> and <scene name='pdbligand=URF:'>URF</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=1UPF OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[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 26: / Line 26: @@
 [[Category: transferase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 04:17:09 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:26:59 2008''