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3kr3

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3kr3, resolution 2.20Å ()
Ligands:
Gene: IGF-II, IGF2, PP1446 (Homo sapiens)


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal structure of IGF-II antibody complex

Publication Abstract from PubMed

Elevated expression of insulin-like growth factor-II (IGF-II) is frequently observed in a variety of human malignancies, including breast, colon, and liver cancer. As IGF-II can deliver a mitogenic signal through both IGF-IR and an alternately spliced form of the insulin receptor (IR-A), neutralizing the biological activity of this growth factor directly is a potential alternative option to IGF-IR-directed agents. Using a Fab-displaying phage library and a biotinylated precursor form of IGF-II (1-104 amino acids) as a target, we isolated Fabs specific for the E-domain COOH-terminal extension form of IGF-II and for mature IGF-II. One of these Fabs that bound to both forms of IGF-II was reformatted into a full-length IgG, expressed, purified, and subjected to further analysis. This antibody (DX-2647) displayed a very high affinity for IGF-II/IGF-IIE (K(D) value of 49 and 10 pmol/L, respectively) compared with IGF-I (approximately 10 nmol/L) and blocked binding of IGF-II to IGF-IR, IR-A, a panel of insulin-like growth factor-binding proteins, and the mannose-6-phosphate receptor. A crystal complex of the parental Fab of DX-2647 bound to IGF-II was resolved to 2.2 A. DX-2647 inhibited IGF-II and, to a lesser extent, IGF-I-induced receptor tyrosine phosphorylation, cellular proliferation, and both anchorage-dependent and anchorage-independent colony formation in various cell lines. In addition, DX-2647 slowed tumor progression in the Hep3B xenograft model, causing decreased tumoral CD31 staining as well as reduced IGF-IIE and IGF-IR phosphorylation levels. Therefore, DX-2647 offers an alternative approach to targeting IGF-IR, blocking IGF-II signaling through both IGF-IR and IR-A.

A human monoclonal antibody against insulin-like growth factor-II blocks the growth of human hepatocellular carcinoma cell lines in vitro and in vivo., Dransfield DT, Cohen EH, Chang Q, Sparrow LG, Bentley JD, Dolezal O, Xiao X, Peat TS, Newman J, Pilling PA, Phan T, Priebe I, Brierley GV, Kastrapeli N, Kopacz K, Martik D, Wassaf D, Rank D, Conley G, Huang Y, Adams TE, Cosgrove L, Mol Cancer Ther. 2010 Jun;9(6):1809-19. Epub 2010 Jun 1. PMID:20515953

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[IGF2_HUMAN] Epigenetic changes of DNA hypomethylation in IGF2 are a cause of Silver-Russell syndrome (SRS) [MIM:180860]. A clinically heterogeneous condition characterized by severe intrauterine growth retardation, poor postnatal growth, craniofacial features such as a triangular shaped face and a broad forehead, body asymmetry, and a variety of minor malformations. The phenotypic expression changes during childhood and adolescence, with the facial features and asymmetry usually becoming more subtle with age.[1]

Function

[IGF2_HUMAN] The insulin-like growth factors possess growth-promoting activity. In vitro, they are potent mitogens for cultured cells. IGF-II is influenced by placental lactogen and may play a role in fetal development.[2] Preptin undergoes glucose-mediated co-secretion with insulin, and acts as physiological amplifier of glucose-mediated insulin secretion. Exhibits osteogenic properties by increasing osteoblast mitogenic activity through phosphoactivation of MAPK1 and MAPK3.[3]

About this Structure

3kr3 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Dransfield DT, Cohen EH, Chang Q, Sparrow LG, Bentley JD, Dolezal O, Xiao X, Peat TS, Newman J, Pilling PA, Phan T, Priebe I, Brierley GV, Kastrapeli N, Kopacz K, Martik D, Wassaf D, Rank D, Conley G, Huang Y, Adams TE, Cosgrove L. A human monoclonal antibody against insulin-like growth factor-II blocks the growth of human hepatocellular carcinoma cell lines in vitro and in vivo. Mol Cancer Ther. 2010 Jun;9(6):1809-19. Epub 2010 Jun 1. PMID:20515953 doi:10.1158/1535-7163.MCT-09-1134
  1. Bartholdi D, Krajewska-Walasek M, Ounap K, Gaspar H, Chrzanowska KH, Ilyana H, Kayserili H, Lurie IW, Schinzel A, Baumer A. Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. J Med Genet. 2009 Mar;46(3):192-7. doi: 10.1136/jmg.2008.061820. Epub 2008 Dec 9. PMID:19066168 doi:10.1136/jmg.2008.061820
  2. Cornish J, Callon KE, Bava U, Watson M, Xu X, Lin JM, Chan VA, Grey AB, Naot D, Buchanan CM, Cooper GJ, Reid IR. Preptin, another peptide product of the pancreatic beta-cell, is osteogenic in vitro and in vivo. Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E117-22. Epub 2006 Aug 15. PMID:16912056 doi:10.1152/ajpendo.00642.2005
  3. Cornish J, Callon KE, Bava U, Watson M, Xu X, Lin JM, Chan VA, Grey AB, Naot D, Buchanan CM, Cooper GJ, Reid IR. Preptin, another peptide product of the pancreatic beta-cell, is osteogenic in vitro and in vivo. Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E117-22. Epub 2006 Aug 15. PMID:16912056 doi:10.1152/ajpendo.00642.2005

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