2aoa
From Proteopedia
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|PDB= 2aoa |SIZE=350|CAPTION= <scene name='initialview01'>2aoa</scene>, resolution 1.99Å | |PDB= 2aoa |SIZE=350|CAPTION= <scene name='initialview01'>2aoa</scene>, resolution 1.99Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=S1S:2-(4-((9S,10S,14S,Z)-18-(2-AMINO-2-OXOETHYL)-9-(CARBOXYMETHYL)-14-(NAPHTHALEN-1-YLMETHYL)-8,17,20-TRIOXO-7,16,19-TRIAZASPIRO[5.14]ICOS-11-EN-10-YL)PHENYL)MALONIC+ACID'>S1S | + | |LIGAND= <scene name='pdbligand=P33:3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL'>P33</scene>, <scene name='pdbligand=S1S:2-(4-((9S,10S,14S,Z)-18-(2-AMINO-2-OXOETHYL)-9-(CARBOXYMETHYL)-14-(NAPHTHALEN-1-YLMETHYL)-8,17,20-TRIOXO-7,16,19-TRIAZASPIRO[5.14]ICOS-11-EN-10-YL)PHENYL)MALONIC+ACID'>S1S</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= GRB2, ASH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= GRB2, ASH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2aoa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2aoa OCA], [http://www.ebi.ac.uk/pdbsum/2aoa PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2aoa RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==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. | 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:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=100790 100790]], Haddad syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=100790 100790]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Shi, Z D.]] | [[Category: Shi, Z D.]] | ||
[[Category: Waugh, D S.]] | [[Category: Waugh, D S.]] | ||
| - | [[Category: P33]] | ||
| - | [[Category: S1S]] | ||
[[Category: domain-swapped]] | [[Category: domain-swapped]] | ||
[[Category: grb2 sh2]] | [[Category: grb2 sh2]] | ||
[[Category: peptide mimetic]] | [[Category: peptide mimetic]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:55:13 2008'' |
Revision as of 22:55, 30 March 2008
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| , resolution 1.99Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Gene: | GRB2, ASH (Homo sapiens) | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain
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.
About this Structure
2AOA is a Single protein structure of sequence from Homo sapiens. 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 Mon Mar 31 01:55:13 2008
