2fgi
From Proteopedia
(New page: 200px<br /> <applet load="2fgi" size="450" color="white" frame="true" align="right" spinBox="true" caption="2fgi, resolution 2.5Å" /> '''CRYSTAL STRUCTURE OF...) |
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caption="2fgi, resolution 2.5Å" /> | caption="2fgi, resolution 2.5Å" /> | ||
'''CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF FGF RECEPTOR 1 IN COMPLEX WITH INHIBITOR PD173074'''<br /> | '''CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF FGF RECEPTOR 1 IN COMPLEX WITH INHIBITOR PD173074'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is an essential physiological process in development, yet also plays a | + | Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is an essential physiological process in development, yet also plays a major role in the progression of human diseases such as diabetic retinopathy, atherosclerosis and cancer. The effects of the most potent angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin and fibroblast growth factor (FGF) are mediated through cell surface receptors that possess intrinsic protein tyrosine kinase activity. In this report, we describe a synthetic compound of the pyrido[2,3-d]pyrimidine class, designated PD 173074, that selectively inhibits the tyrosine kinase activities of the FGF and VEGF receptors. We show that systemic administration of PD 173074 in mice can effectively block angiogenesis induced by either FGF or VEGF with no apparent toxicity. To elucidate the determinants of selectivity, we have determined the crystal structure of PD 173074 in complex with the tyrosine kinase domain of FGF receptor 1 at 2.5 A resolution. A high degree of surface complementarity between PD 173074 and the hydrophobic, ATP-binding pocket of FGF receptor 1 underlies the potency and selectivity of this inhibitor. PD 173074 is thus a promising candidate for a therapeutic angiogenesis inhibitor to be used in the treatment of cancer and other diseases whose progression is dependent upon new blood vessel formation. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2FGI 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 PD1 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http:// | + | 2FGI 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=PD1:'>PD1</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FGI OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
| - | [[Category: Eliseenkova, A | + | [[Category: Eliseenkova, A V.]] |
[[Category: Froum, S.]] | [[Category: Froum, S.]] | ||
[[Category: Green, D.]] | [[Category: Green, D.]] | ||
| - | [[Category: Hamby, J | + | [[Category: Hamby, J M.]] |
| - | [[Category: Hubbard, S | + | [[Category: Hubbard, S R.]] |
| - | [[Category: Lu, G | + | [[Category: Lu, G H.]] |
[[Category: Mohammadi, M.]] | [[Category: Mohammadi, M.]] | ||
| - | [[Category: Panek, R | + | [[Category: Panek, R L.]] |
[[Category: Schlessinger, J.]] | [[Category: Schlessinger, J.]] | ||
[[Category: Schroeder, M.]] | [[Category: Schroeder, M.]] | ||
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[[Category: tyrosine-protein kinase]] | [[Category: tyrosine-protein kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:21:08 2008'' |
Revision as of 15:21, 21 February 2008
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CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF FGF RECEPTOR 1 IN COMPLEX WITH INHIBITOR PD173074
Contents |
Overview
Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is an essential physiological process in development, yet also plays a major role in the progression of human diseases such as diabetic retinopathy, atherosclerosis and cancer. The effects of the most potent angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin and fibroblast growth factor (FGF) are mediated through cell surface receptors that possess intrinsic protein tyrosine kinase activity. In this report, we describe a synthetic compound of the pyrido[2,3-d]pyrimidine class, designated PD 173074, that selectively inhibits the tyrosine kinase activities of the FGF and VEGF receptors. We show that systemic administration of PD 173074 in mice can effectively block angiogenesis induced by either FGF or VEGF with no apparent toxicity. To elucidate the determinants of selectivity, we have determined the crystal structure of PD 173074 in complex with the tyrosine kinase domain of FGF receptor 1 at 2.5 A resolution. A high degree of surface complementarity between PD 173074 and the hydrophobic, ATP-binding pocket of FGF receptor 1 underlies the potency and selectivity of this inhibitor. PD 173074 is thus a promising candidate for a therapeutic angiogenesis inhibitor to be used in the treatment of cancer and other diseases whose progression is dependent upon new blood vessel formation.
Disease
Known diseases associated with this structure: Atopic dermatitis, susceptibility to OMIM:[135940], Ichthyosis vulgaris OMIM:[135940], Jackson-Weiss syndrome OMIM:[136350], Kallmann syndrome 2 OMIM:[136350], Pfeiffer syndrome OMIM:[136350]
About this Structure
2FGI is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.
Reference
Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain., Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, Eliseenkova AV, Green D, Schlessinger J, Hubbard SR, EMBO J. 1998 Oct 15;17(20):5896-904. PMID:9774334
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