3lw0 | pdb_00003lw0

IGF-1RK in complex with ligand MSC1609119A-1

spinqualitylabelsall models 3lw0, resolution 1.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3lw0 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CCX, GOL Gene: IGF1R (HUMAN) Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [IGF1R_HUMAN] Defects in IGF1R are a cause of insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450]. It is a disorder characterized by intrauterine growth retardation and poor postnatal growth accompanied with increased plasma IGF1. Function [IGF1R_HUMAN] Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R. When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Targeting allosteric protein sites is a promising approach to interfere selectively with cellular signaling cascades. We have discovered a novel class of allosteric insulin-like growth factor-I receptor (IGF-1R) inhibitors. 3-Cyano-1H-indole-7-carboxylic acid {1-[4-(5-cyano-1H-indol-3-yl)butyl]piperidin-4-yl}amide (10) was found with nanomolar biochemical, micromolar, cellular IGF-1R activity and no relevant interference with cellular insulin receptor signaling up to 30 muM. The allosteric binding site was characterized by X-ray crystallographic studies, and the structural information was used to explain the unique mode of action of this new class of inhibitors. Allosteric IGF-1R Inhibitors.,Heinrich T, Gradler U, Bottcher H, Blaukat A, Shutes A ACS Med Chem Lett. 2010 May 18;1(5):199-203. doi: 10.1021/ml100044h. eCollection , 2010 Aug 12. PMID:24900194 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Insulin-like growth factor receptor

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