2aoa
From Proteopedia
(New page: 200px<br /> <applet load="2aoa" size="450" color="white" frame="true" align="right" spinBox="true" caption="2aoa, resolution 1.99Å" /> '''Crystal structures ...) |
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caption="2aoa, resolution 1.99Å" /> | caption="2aoa, resolution 1.99Å" /> | ||
'''Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain'''<br /> | '''Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The high-affinity binding of the growth factor receptor-bound protein 2 | + | The high-affinity binding of the growth factor receptor-bound protein 2 (Grb2) SH2 domain to tyrosine-phosphorylated cytosolic domains of receptor tyrosine kinases (RTKs) is an attractive target for therapeutic intervention in many types of cancer. We report here two crystal forms of a complex between the Grb2 SH2 domain and a potent non-phosphorus-containing macrocyclic peptide mimetic that exhibits significant anti-proliferative effects against erbB-2-dependent breast cancers. This agent represents a "second generation" inhibitor with greatly improved binding affinity and bio-availability compared to its open-chain counterpart. The structures were determined at 2.0A and 1.8A with one and two domain-swapped dimers per asymmetric unit, respectively. The mode of binding and specific interactions between the protein and the inhibitor provide insight into the high potency of this class of macrocylic compounds and may aid in further optimization as part of the iterative rational drug design process. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2AOA 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 S1S and P33 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 2AOA 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=S1S:'>S1S</scene> and <scene name='pdbligand=P33:'>P33</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AOA OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Burke, T | + | [[Category: Burke, T R.]] |
[[Category: Phan, J.]] | [[Category: Phan, J.]] | ||
| - | [[Category: Shi, Z | + | [[Category: Shi, Z D.]] |
| - | [[Category: Waugh, D | + | [[Category: Waugh, D S.]] |
[[Category: P33]] | [[Category: P33]] | ||
[[Category: S1S]] | [[Category: S1S]] | ||
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[[Category: peptide mimetic]] | [[Category: peptide mimetic]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:29:18 2008'' |
Revision as of 14:29, 21 February 2008
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Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain
Contents |
Overview
The high-affinity binding of the growth factor receptor-bound protein 2 (Grb2) SH2 domain to tyrosine-phosphorylated cytosolic domains of receptor tyrosine kinases (RTKs) is an attractive target for therapeutic intervention in many types of cancer. We report here two crystal forms of a complex between the Grb2 SH2 domain and a potent non-phosphorus-containing macrocyclic peptide mimetic that exhibits significant anti-proliferative effects against erbB-2-dependent breast cancers. This agent represents a "second generation" inhibitor with greatly improved binding affinity and bio-availability compared to its open-chain counterpart. The structures were determined at 2.0A and 1.8A with one and two domain-swapped dimers per asymmetric unit, respectively. The mode of binding and specific interactions between the protein and the inhibitor provide insight into the high potency of this class of macrocylic compounds and may aid in further optimization as part of the iterative rational drug design process.
Disease
Known diseases associated with this structure: Central hypoventilation syndrome, congenital OMIM:[100790], Haddad syndrome OMIM:[100790]
About this Structure
2AOA is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain., Phan J, Shi ZD, Burke TR Jr, Waugh DS, J Mol Biol. 2005 Oct 14;353(1):104-15. PMID:16165154
Page seeded by OCA on Thu Feb 21 16:29:18 2008
Categories: Homo sapiens | Single protein | Burke, T R. | Phan, J. | Shi, Z D. | Waugh, D S. | P33 | S1S | Domain-swapped | Grb2 sh2 | Peptide mimetic
