Structural Research of Vascular Endothelial Growth Factor Receptors

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Vascular endothelial growth factor (VEGF) binds to a variety of membrane receptors (VEGFR) to regulate vertebrate biological responses, including vasculogenesis, vascular development, and lymphangiogenesis. VEGFR is a widely researched membrane-bound receptor tyrosine kinase protein, of which VEGFR-1 is required for hematopoietic stem cell recruitment as well as monocyte and macrophage migration, VEGFR-2 regulates vascular endothelial function, and VEGFR-3 regulates lymphatic endothelial function. In recent years, research has revealed that VEGF-VEGFR dysregulation is involved in many diseases, especially cancer. Therefore, research on VEGF-VEGFR will help to develop therapeutic approaches for such diseases.

Overall structural analysis of VEGFR

The kinase structural domains of VEGFR are conserved and have high sequence identity. Most VEGFRs display similar primary structures, including seven immunoglobulin (Ig)-like domains, a short α-helical transmembrane domain, cytoplasmic near-membrane regions, and a tyrosine kinase (TK) domain linked to a flexible carboxyl-terminal linkage. The binding of VEGFRs to homologous ligands triggers the formation of homodimers, which activate cellular signaling pathways that lead to a wide range of cellular functions.

Advances in structural research of VEGF-VEGFR complexes

To date, many structural studies of the VEGF/VEGFR complex based on single-particle electron microscopy, small-angle X-ray scattering, and X-ray crystallography have shown how the ligand binds to the Ig structural domain at the distal end of the membrane. The structures show the presence of two 1:1 complexes in the asymmetric unit and two receptors linked by the dimeric VEGF-A bound to the Ig structural domain. The research also shows that homotypic receptor-receptor contacts in Ig structural domains 4-7 increase the binding affinity of VEGFR-1 ECD to VEGF-A.

Figure 1. A schematic representation of full-length VEGFR-1 with VEGF-A. (Kaufman NEM, et al., 2021)

Protein	Organism	Method	Resolution	PDB Entry ID
Dimeric G-quadruplex DNA formed in the proximal promoter of VEGFR-2	DNA molecule	SOLUTION NMR	/	7XH3
Dimeric G-quadruplex DNA formed in the proximal promoter of VEGFR-2	synthetic construct	SOLUTION NMR	/	7XFV
G-quadruplex formed in vegfr-2 proximal promoter sequence	synthetic construct	SOLUTION NMR	/	5ZEV
VEGF-A in complex with VEGFR-1 domains D1-6	Homo sapiens	X-ray diffraction	4 Å	5T89
VEGFR-1 domain 2 in presence of Zn	Homo sapiens	X-ray diffraction	2.055 Å	4CKV
VEGFR-3 extracellular domains D4-5	Homo sapiens	X-ray diffraction	2.5 Å	4BSJ
VEGFR-1 domain 2 in presence of Cobalt	Homo sapiens	X-ray diffraction	2 Å	4CL7
VEGFR-1 domain 2 in presence of CU	Homo sapiens	X-ray diffraction	1.995 Å	5ABD
VEGFR-2/VEGF-E complex	Homo sapiens	X-ray diffraction	3.205 Å	3V6B
VEGF-C in complex with VEGFR-3 domains D1-2	Homo sapiens	X-ray diffraction	4.201 Å	4BSK
The Binding of VEGF-B by VEGFR-1D2	Homo sapiens	X-ray diffraction	2.71 Å	2XAC
The trimeric mutant TM domain of VEGFR2 receptor	Homo sapiens	SOLUTION NMR	/	2MET
The VEGFR2 kinase domain in complex with axitinib (AG-013736)	Homo sapiens	X-ray diffraction	1.95 Å	4AG8
VEGFR2 kinase domain in complex with PF- 00337210	Homo sapiens	X-ray diffraction	1.5 Å	2XIR
VEGFR2 (Juxtamembrane and Kinase Domains) in complex with sorafenib (BAY 43-9006)	Homo sapiens	X-ray diffraction	2.03 Å	4ASO
VEGFR2 in complex with a 3,4,5-trimethoxy aniline containing pyrimidine	Homo sapiens	X-ray diffraction	2.15 Å	3CJF
VEGFR IN complex with tivozanib (AV-951)	Homo sapiens	X-ray diffraction	1.83 Å	4ASE
VEGFR1 in complex with N-(4-Chlorophenyl)-2-((pyridin-4-ylmethyl) amino) benzamide	Homo sapiens	X-ray diffraction	2.7 Å	3HNG
The dimeric VEGFR2 membrane domain	Homo sapiens	SOLUTION NMR	/	2M59
The mutant dimeric TM domain of VEGFR2 receptor	Homo sapiens	SOLUTION NMR	/	2MEU
Vegfr2 with a benzimidazole-urea inhibitor	Homo sapiens	X-ray diffraction	2.05 Å	2OH4
PlGF in complex with domain 2 of VEGFR1	Homo sapiens	X-ray diffraction	2.45 Å	1RV6
VEGFR-2 domains 4-5 in complex with DARPin D4b	Homo sapiens	X-ray diffraction	2.38 Å	5OYJ

Table 1. Structural research of the vascular endothelial growth factor receptors.

Understanding the structure and function of membrane proteins, such as vascular endothelial growth factor receptors, is essential for the development of new drugs and therapies for the treatment of related diseases, and Creative Biostructure is a leading provider of structural analysis services for membrane proteins. Our team of experts uses X-ray crystallography, cryo-electron microscopy (cryo-EM), and NMR spectroscopy to determine the three-dimensional structure of membrane proteins and understand their function.

If you are interested in gaining a deeper understanding of the structure of membrane proteins and other biomolecules, our team of experts is the right choice. With many years of experience and a wealth of knowledge, we are always available to discuss your research requirements and provide you with the best solution for your project. Contact us today to learn more about our comprehensive structural analysis services and how we can help take your research to the next level.

References

Kaufman NEM, et al. Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR). Molecules. 2021. 26(4): 1076.
Holmes K, et al. Vascular endothelial growth factor receptor-2: structure, function, intracellular signaling, and therapeutic inhibition. Cell Signal. 2007. 19(10): 2003-2012.
Park SA, et al. Structure and function of vascular endothelial growth factor and its receptor system. BMB Rep. 2018. 51(2): 73-78.
Shaik F, et al. Structural Basis for Vascular Endothelial Growth Factor Receptor Activation and Implications for Disease Therapy. Biomolecules. 2020. 10(12): 1673.