Epithelial discoidin domain-containing receptor

From Proteopedia

Contents 1 Function 2 Disease 3 Relevance 4 Structural highlights Function Epithelial discoidin domain-containing receptor (DDR1 and DDR2) are extracellular matrix-sensing Receptor tyrosine kinases which are activated by collagen and are expressed in bronchial epithelium. They are responsible for maintaining the normal structure of skin and kidney epithelia[1]. DDR1 and DDR2 function as sensors for extracellular matrix and to regulate a wide range of cell functions from migration and proliferation to cytokine secretion and extracellular matrix homeostasis/remodeling[2]. See also Kinase-linked, enzyme-linked and related receptors. Disease DDR1 promotes inflammation in atherosclerosis, lung fibrosis and kidney injury[2] Relevance DDR1 plays a consequential role in a variety of cancers[3]. A low DDR1/high DDR2 profile is associated with high tumor grade and may identify invasive carcinomas with worse prognosis[4]. Structural highlights DDR1 contains a discoidin domain. This domain is about 150 amino acid long and is found in many blood coagulation factors. The structure of the complex between DDR1 and imatinib shows hydrogen bonds interactions between the anti-cancer drug and the kinase domain including bonds with the kinase allosteric site Asp-Phe-Gly (DFG motif)[5]. Water molecules are shown as red spheres.

Jmol._Canvas2D (Jmol) "jmolApplet1"[x] spinqualitylabelsall models Human DDR1 kinase domain complex with imatinib and ethylene glycol (PDB code 4bkj) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

3D structures of epithelial discoidin domain-containing receptor

Updated on 19-January-2022

Epithelial discoidin domain-containing receptor 1; Domains – discoidin 26-186; ligand-binding 283-385; kinase 543-913

5bvk, 6y23 – hDDR1 kinase domain – human

3zos, 4bkj, 6bsd – hDDR1 kinase domain + cancer drug

6few – hDDR1 kinase domain + alport syndrome drug

6fex, 6fil,6fin, 6fio, 6fiq – hDDR1 kinase domain (mutant) + alport syndrome drug

4ckr, 5bvn, 5bvo, 5bvw, 5fdp, 5fdx, 6brj, 6gwr, 6hp9, 7bcm, 7be6 – hDDR1 kinase domain + inhibitor

4ag4 – hDDR1 29-367 domain + antibody

Epithelial discoidin domain-containing receptor 2

2z4f – hDDR2 discoidin domain – NMR

2wuh – hDDR2 discoidin domain + collagen

6fer, 7aym – hDDR2 kinase domain + inhibitor

References

1. ↑ Roberts ME, Magowan L, Hall IP, Johnson SR. Discoidin domain receptor 1 regulates bronchial epithelial repair and matrix metalloproteinase production. Eur Respir J. 2011 Jun;37(6):1482-93. doi: 10.1183/09031936.00039710. Epub 2010, Sep 30. PMID:20884741 doi:http://dx.doi.org/10.1183/09031936.00039710
2. ↑ ^{2.0 2.1} Borza CM, Pozzi A. Discoidin domain receptors in disease. Matrix Biol. 2014 Feb;34:185-92. doi: 10.1016/j.matbio.2013.12.002. Epub 2013 Dec, 19. PMID:24361528 doi:http://dx.doi.org/10.1016/j.matbio.2013.12.002
3. ↑ Song J, Chen X, Bai J, Liu Q, Li H, Xie J, Jing H, Zheng J. Discoidin domain receptor 1 (DDR1), a promising biomarker, induces epithelial to mesenchymal transition in renal cancer cells. Tumour Biol. 2016 Aug;37(8):11509-21. doi: 10.1007/s13277-016-5021-2. Epub 2016, Mar 28. PMID:27020590 doi:http://dx.doi.org/10.1007/s13277-016-5021-2
4. ↑ Toy KA, Valiathan RR, Nunez F, Kidwell KM, Gonzalez ME, Fridman R, Kleer CG. Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer. Breast Cancer Res Treat. 2015 Feb;150(1):9-18. doi: 10.1007/s10549-015-3285-7., Epub 2015 Feb 10. PMID:25667101 doi:http://dx.doi.org/10.1007/s10549-015-3285-7
5. ↑ Canning P, Tan L, Chu K, Lee SW, Gray NS, Bullock AN. Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors. J Mol Biol. 2014 Apr 22. pii: S0022-2836(14)00198-3. doi:, 10.1016/j.jmb.2014.04.014. PMID:24768818 doi:http://dx.doi.org/10.1016/j.jmb.2014.04.014