5OYJ

Crystal structure of VEGFR-2 domains 4-5 in complex with DARPin D4b

Summary for 5OYJ

• Entry DOI: 10.2210/pdb5oyj/pdb
• Related PRD ID: PRD_900006
• Descriptor: DARPin D4b, Vascular endothelial growth factor receptor 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: glycoprotein receptor kinase designed ankyrin repeat protein angiogenesis, signaling protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 4
• Total formula weight: 93563.33

Authors

Piscitelli, C.L.,Thieltges, K.M.,Markovic-Mueller, S.,Binz, H.K.,Ballmer-Hofer, K. (deposition date: 2017-09-10, release date: 2018-03-14, Last modification date: 2024-11-13)

Primary citation

Thieltges, K.M.,Avramovic, D.,Piscitelli, C.L.,Markovic-Mueller, S.,Binz, H.K.,Ballmer-Hofer, K.
Characterization of a drug-targetable allosteric site regulating vascular endothelial growth factor signaling.
Angiogenesis, 21:533-543, 2018

PubMed Abstract: Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases (VEGFRs). The extracellular domain of VEGFRs consists of seven Ig-homology domains, of which D2-3 form the ligand-binding site, while the membrane proximal domains D4-7 are involved in homotypic interactions in ligand-bound receptor dimers. Based on low-resolution structures, we identified allosteric sites in D4-5 and D7 of vascular endothelial growth factor receptor 2 (VEGFR-2) accomplishing regulatory functions. Allosteric inhibition of VEGFR-2 signaling represents an attractive option for the treatment of neovascular diseases. We showed earlier that DARPin binders to domains D4 or D7 are potent VEGFR-2 inhibitors. Here we investigated in detail the allosteric inhibition mechanism of the domain D4 binding inhibitor D4b. The 2.38 Å crystal structure of D4b in complex with VEGFR-2 D4-5, the first high-resolution structure of this VEGFR-2 segment, indicates steric hindrance by D4b as the mechanism of inhibition of receptor activation. At the cellular level, D4b triggered quantitative internalization of VEGFR-2 in the absence of ligand and thus clearance of VEGFR-2 from the surface of endothelial cells. The allosteric VEGFR-2 inhibition was sufficiently strong to efficiently inhibit the growth of human endothelial cells at suboptimal dose in a mouse xenograft model in vivo, underlining the therapeutic potential of the approach.

PubMed: 29502220
DOI: 10.1007/s10456-018-9606-9

Experimental method

X-RAY DIFFRACTION (2.38 Å)