1r6k
From Proteopedia
(New page: 200px<br /><applet load="1r6k" size="450" color="white" frame="true" align="right" spinBox="true" caption="1r6k, resolution 2.50Å" /> '''HPV11 E2 TAD crystal...) |
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| - | [[Image:1r6k.gif|left|200px]]<br /><applet load="1r6k" size=" | + | [[Image:1r6k.gif|left|200px]]<br /><applet load="1r6k" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1r6k, resolution 2.50Å" /> | caption="1r6k, resolution 2.50Å" /> | ||
'''HPV11 E2 TAD crystal structure'''<br /> | '''HPV11 E2 TAD crystal structure'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Interaction between the E2 protein and E1 helicase of human | + | Interaction between the E2 protein and E1 helicase of human papillomaviruses (HPVs) is essential for the initiation of viral DNA replication. We recently described a series of small molecules that bind to the N-terminal transactivation domain (TAD) of HPV type 11 E2 and inhibits its interaction with E1 in vitro and in cellular assays. Here we report the crystal structures of both the HPV11 TAD and of a complex between this domain and an inhibitor, at 2.5- and 2.4-A resolution, respectively. The HPV11 TAD structure is very similar to that of the analogous domain of HPV16. Inhibitor binding caused no significant alteration of the protein backbone, but movements of several amino acid side chains at the binding site, in particular those of Tyr-19, His-32, Leu-94, and Glu-100, resulted in the formation of a deep hydrophobic pocket that accommodates the indandione moiety of the inhibitor. Mutational analysis provides functional evidence for specific interactions between Tyr-19 and E1 and between His-32 and the inhibitor. A second inhibitor molecule is also present at the binding pocket. Although evidence is presented that this second molecule makes only weak interactions with the protein and is likely an artifact of crystallization, its presence defines additional regions of the binding pocket that could be exploited to design more potent inhibitors. |
==About this Structure== | ==About this Structure== | ||
| - | 1R6K is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_papillomavirus_type_33 Human papillomavirus type 33]. Full crystallographic information is available from [http:// | + | 1R6K is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_papillomavirus_type_33 Human papillomavirus type 33]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1R6K OCA]. |
==Reference== | ==Reference== | ||
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[[Category: papillomavirus; e2 tad; tad domain; x-ray structure; transcription; replication]] | [[Category: papillomavirus; e2 tad; tad domain; x-ray structure; transcription; replication]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:47:39 2008'' |
Revision as of 12:47, 21 February 2008
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HPV11 E2 TAD crystal structure
Overview
Interaction between the E2 protein and E1 helicase of human papillomaviruses (HPVs) is essential for the initiation of viral DNA replication. We recently described a series of small molecules that bind to the N-terminal transactivation domain (TAD) of HPV type 11 E2 and inhibits its interaction with E1 in vitro and in cellular assays. Here we report the crystal structures of both the HPV11 TAD and of a complex between this domain and an inhibitor, at 2.5- and 2.4-A resolution, respectively. The HPV11 TAD structure is very similar to that of the analogous domain of HPV16. Inhibitor binding caused no significant alteration of the protein backbone, but movements of several amino acid side chains at the binding site, in particular those of Tyr-19, His-32, Leu-94, and Glu-100, resulted in the formation of a deep hydrophobic pocket that accommodates the indandione moiety of the inhibitor. Mutational analysis provides functional evidence for specific interactions between Tyr-19 and E1 and between His-32 and the inhibitor. A second inhibitor molecule is also present at the binding pocket. Although evidence is presented that this second molecule makes only weak interactions with the protein and is likely an artifact of crystallization, its presence defines additional regions of the binding pocket that could be exploited to design more potent inhibitors.
About this Structure
1R6K is a Single protein structure of sequence from Human papillomavirus type 33. Full crystallographic information is available from OCA.
Reference
Crystal structure of the E2 transactivation domain of human papillomavirus type 11 bound to a protein interaction inhibitor., Wang Y, Coulombe R, Cameron DR, Thauvette L, Massariol MJ, Amon LM, Fink D, Titolo S, Welchner E, Yoakim C, Archambault J, White PW, J Biol Chem. 2004 Feb 20;279(8):6976-85. Epub 2003 Nov 22. PMID:14634007
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