1zlx
From Proteopedia
(New page: 200px<br /> <applet load="1zlx" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zlx, resolution 2.2Å" /> '''The apo structure of...) |
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| - | [[Image:1zlx.gif|left|200px]]<br /> | + | [[Image:1zlx.gif|left|200px]]<br /><applet load="1zlx" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1zlx, resolution 2.2Å" /> | caption="1zlx, resolution 2.2Å" /> | ||
'''The apo structure of human glycinamide ribonucleotide transformylase'''<br /> | '''The apo structure of human glycinamide ribonucleotide transformylase'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Glycinamide ribonucleotide transformylase (GART; | + | Glycinamide ribonucleotide transformylase (GART; 10-formyltetrahydrofolate:5'-phosphoribosylglycinamide formyltransferase, EC 2.1.2.2), an essential enzyme in de novo purine biosynthesis, has been a chemotherapeutic target for several decades. The three-dimensional structure of the GART domain from the human trifunctional enzyme has been solved by X-ray crystallography. Models of the apoenzyme, and a ternary complex with the 10-formyl-5,8-dideazafolate cosubstrate and a glycinamide ribonucleotide analogue, hydroxyacetamide ribonucleotide [alpha,beta-N-(hydroxyacetyl)-d-ribofuranosylamine], are reported to 2.2 and 2.07 A, respectively. The model of the apoenzyme represents the first structure of GART, from any source, with a completely unoccupied substrate and cosubstrate site, while the ternary complex is the first structure of the human GART domain that is bound at both the substrate and cosubstrate sites. A comparison of the two models therefore reveals subtle structural differences that reflect substrate and cosubstrate binding effects and implies roles for the invariant residues Gly 133, Gly 146, and His 137. Preactivation of the DDF formyl group appears to be key for catalysis, and structural flexibility of the active end of the substrate may facilitate nucleophilic attack. A change in pH, rather than folate binding, correlates with movement of the folate binding loop, whereas the phosphate binding loop position does not vary with pH. The electrostatic surface potentials of the human GART domain and Escherichia coli enzyme explain differences in the binding affinity of polyglutamylated folates, and these differences have implications to future chemotherapeutic agent design. |
==About this Structure== | ==About this Structure== | ||
| - | 1ZLX 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 GOL as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphoribosylglycinamide_formyltransferase Phosphoribosylglycinamide formyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.2.2 2.1.2.2] Full crystallographic information is available from [http:// | + | 1ZLX 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=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphoribosylglycinamide_formyltransferase Phosphoribosylglycinamide formyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.2.2 2.1.2.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZLX OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Phosphoribosylglycinamide formyltransferase]] | [[Category: Phosphoribosylglycinamide formyltransferase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Caperelli, C | + | [[Category: Caperelli, C A.]] |
| - | [[Category: Dahms, T | + | [[Category: Dahms, T E.]] |
| - | [[Category: Giroux, E | + | [[Category: Giroux, E L.]] |
[[Category: Sainz, G.]] | [[Category: Sainz, G.]] | ||
| - | [[Category: Smith, J | + | [[Category: Smith, J L.]] |
[[Category: GOL]] | [[Category: GOL]] | ||
[[Category: folate binding loop]] | [[Category: folate binding loop]] | ||
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[[Category: seven stranded beta-pleated sheet]] | [[Category: seven stranded beta-pleated sheet]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:17:00 2008'' |
Revision as of 14:17, 21 February 2008
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The apo structure of human glycinamide ribonucleotide transformylase
Overview
Glycinamide ribonucleotide transformylase (GART; 10-formyltetrahydrofolate:5'-phosphoribosylglycinamide formyltransferase, EC 2.1.2.2), an essential enzyme in de novo purine biosynthesis, has been a chemotherapeutic target for several decades. The three-dimensional structure of the GART domain from the human trifunctional enzyme has been solved by X-ray crystallography. Models of the apoenzyme, and a ternary complex with the 10-formyl-5,8-dideazafolate cosubstrate and a glycinamide ribonucleotide analogue, hydroxyacetamide ribonucleotide [alpha,beta-N-(hydroxyacetyl)-d-ribofuranosylamine], are reported to 2.2 and 2.07 A, respectively. The model of the apoenzyme represents the first structure of GART, from any source, with a completely unoccupied substrate and cosubstrate site, while the ternary complex is the first structure of the human GART domain that is bound at both the substrate and cosubstrate sites. A comparison of the two models therefore reveals subtle structural differences that reflect substrate and cosubstrate binding effects and implies roles for the invariant residues Gly 133, Gly 146, and His 137. Preactivation of the DDF formyl group appears to be key for catalysis, and structural flexibility of the active end of the substrate may facilitate nucleophilic attack. A change in pH, rather than folate binding, correlates with movement of the folate binding loop, whereas the phosphate binding loop position does not vary with pH. The electrostatic surface potentials of the human GART domain and Escherichia coli enzyme explain differences in the binding affinity of polyglutamylated folates, and these differences have implications to future chemotherapeutic agent design.
About this Structure
1ZLX is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Phosphoribosylglycinamide formyltransferase, with EC number 2.1.2.2 Full crystallographic information is available from OCA.
Reference
The apo and ternary complex structures of a chemotherapeutic target: human glycinamide ribonucleotide transformylase., Dahms TE, Sainz G, Giroux EL, Caperelli CA, Smith JL, Biochemistry. 2005 Jul 26;44(29):9841-50. PMID:16026156
Page seeded by OCA on Thu Feb 21 16:17:00 2008
Categories: Homo sapiens | Phosphoribosylglycinamide formyltransferase | Single protein | Caperelli, C A. | Dahms, T E. | Giroux, E L. | Sainz, G. | Smith, J L. | GOL | Folate binding loop | Modified doubly wound alpha/beta sheet | Mononucleotide binding domain (beta-alpha-beta-alpha-beta) | Phosphate binding loop | Seven stranded beta-pleated sheet
