1k3a
From Proteopedia
(New page: 200px<br /> <applet load="1k3a" size="450" color="white" frame="true" align="right" spinBox="true" caption="1k3a, resolution 2.10Å" /> '''Structure of the In...) |
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| - | [[Image:1k3a.gif|left|200px]]<br /> | + | [[Image:1k3a.gif|left|200px]]<br /><applet load="1k3a" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1k3a" size=" | + | |
caption="1k3a, resolution 2.10Å" /> | caption="1k3a, resolution 2.10Å" /> | ||
'''Structure of the Insulin-like Growth Factor 1 Receptor Kinase'''<br /> | '''Structure of the Insulin-like Growth Factor 1 Receptor Kinase'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The insulin-like growth factor 1 (IGF1) receptor is closely related to the | + | The insulin-like growth factor 1 (IGF1) receptor is closely related to the insulin receptor. However, the unique biological functions of IGF1 receptor make it a target for therapeutic intervention in human cancer. Using its isolated tyrosine kinase domain, we show that the IGF1 receptor is regulated by intermolecular autophosphorylation at three sites within the kinase activation loop. Steady-state kinetic analyses of the isolated phosphorylated forms of the IGF1 receptor kinase (IGF1RK) reveal that each autophosphorylation event increases enzyme turnover number and decreases Km for ATP and peptide. We have determined the 2.1 A-resolution crystal structure of the tris-phosphorylated form of IGF1RK in complex with an ATP analog and a specific peptide substrate. The structure of IGF1RK reveals how the enzyme recognizes peptides containing hydrophobic residues at the P+1 and P+3 positions and how autophosphorylation stabilizes the activation loop in a conformation that facilitates catalysis. Although the nucleotide binding cleft is conserved between IGF1RK and the insulin receptor kinase, sequence differences in the nearby interlobe linker could potentially be exploited for anticancer drug design. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1K3A is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ACP 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:// | + | 1K3A is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ACP:'>ACP</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=1K3A OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Transferase]] | [[Category: Transferase]] | ||
[[Category: Favelyukis, S.]] | [[Category: Favelyukis, S.]] | ||
| - | [[Category: Hubbard, S | + | [[Category: Hubbard, S R.]] |
| - | [[Category: Miller, W | + | [[Category: Miller, W T.]] |
| - | [[Category: Till, J | + | [[Category: Till, J H.]] |
[[Category: ACP]] | [[Category: ACP]] | ||
[[Category: protein kinase]] | [[Category: protein kinase]] | ||
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[[Category: tyrosine phosphorylation]] | [[Category: tyrosine phosphorylation]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:29:44 2008'' |
Revision as of 11:29, 21 February 2008
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Structure of the Insulin-like Growth Factor 1 Receptor Kinase
Contents |
Overview
The insulin-like growth factor 1 (IGF1) receptor is closely related to the insulin receptor. However, the unique biological functions of IGF1 receptor make it a target for therapeutic intervention in human cancer. Using its isolated tyrosine kinase domain, we show that the IGF1 receptor is regulated by intermolecular autophosphorylation at three sites within the kinase activation loop. Steady-state kinetic analyses of the isolated phosphorylated forms of the IGF1 receptor kinase (IGF1RK) reveal that each autophosphorylation event increases enzyme turnover number and decreases Km for ATP and peptide. We have determined the 2.1 A-resolution crystal structure of the tris-phosphorylated form of IGF1RK in complex with an ATP analog and a specific peptide substrate. The structure of IGF1RK reveals how the enzyme recognizes peptides containing hydrophobic residues at the P+1 and P+3 positions and how autophosphorylation stabilizes the activation loop in a conformation that facilitates catalysis. Although the nucleotide binding cleft is conserved between IGF1RK and the insulin receptor kinase, sequence differences in the nearby interlobe linker could potentially be exploited for anticancer drug design.
Disease
Known diseases associated with this structure: Coronary artery disease, susceptibility to OMIM:[147545], Diabetes mellitus, noninsulin-dependent OMIM:[147545], Intrauterine and postnatal growth retardation OMIM:[147370]
About this Structure
1K3A is a Protein complex structure of sequences 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
Structure and autoregulation of the insulin-like growth factor 1 receptor kinase., Favelyukis S, Till JH, Hubbard SR, Miller WT, Nat Struct Biol. 2001 Dec;8(12):1058-63. PMID:11694888
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