alexa Structural Analysis Of Vascular Endothelial Growth Factor Receptors Reveals Drug-targetable Allosteric Sites Regulating Angiogenesis
ISSN: 0974-276X

Journal of Proteomics & Bioinformatics
Open Access

Like us on:
OMICS International organises 3000+ Global Conferenceseries Events every year across USA, Europe & Asia with support from 1000 more scientific Societies and Publishes 700+ Open Access Journals which contains over 50000 eminent personalities, reputed scientists as editorial board members.

Open Access Journals gaining more Readers and Citations

700 Journals and 15,000,000 Readers Each Journal is getting 25,000+ Readers

This Readership is 10 times more when compared to other Subscription Journals (Source: Google Analytics)

Share This Page

Additional Info

Loading
Loading Please wait..
 

9th International Conference on Structural Biology
September 18-20, 2017 Zurich, Switzerland

Kurt Ballmer-Hofer, Sandra Markovic-Mueller, Edward Stuttfeld and Dragana Avramovic
Paul Scherrer Institut, Switzerland
ScientificTracks Abstracts: J Proteomics Bioinform
DOI: 10.4172/0974-276X-C1-100
Abstract
Vascular Endothelial Growth Factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases (RTKs), VEGFR-1, -2, and -3. Partial structures of VEGFR/VEGF complexes based on single particle electron microscopy, small angle X-ray scattering, and X-ray crystallography revealed the location of VEGF binding and the spatial arrangement of individual receptor subdomains. Here we describe the structure of the full-length VEGFR-1 extracellular domain (ECD) in complex with VEGF-A at 4 Å resolution. We combined X-ray crystallography, single particle electron microscopy, and molecular modeling for structure determination and validation. The structure reveals the molecular details of ligand-induced receptor dimerization, in particular of homotypic receptor interactions in Ig-domains 4, 5, and 7. Functional analyses of ligand binding and receptor activation confirm the relevance of these homotypic contacts for receptor activation and identify them as allosteric regulatory sites of VEGFR-1. Based on our structural data we also investigated the function of Ig-domains 4, 5 and 7 in VEGFR-2, the primary receptor driving angiogenesis and vasculogenesis in response to VEGF administration. The basic domain structure of VEGFR-2 is very similar to VEGFR-1, the ECD of both receptors consists of 7 Ig-domains, D1-D7. Mutagenesis studies based on the VEGFR-1structure confirmed that Ig-domains 4 and 7 fulfill an essential regulatory function in receptor activation and may thus represent putative targets for pharmacological intervention. We isolated highly specific antibodies and DARPins (Designed Ankyrin Repeat Proteins) specific for domains 4 or 7. A subset of these reagents efficiently blocked receptor activation and inhibited VEGF-dependent signaling in vitro in endothelial cell cultures. Most importantly, a domain 4-specific DARPin efficiently blocked vessel development also in vivo in a mouse angiogenesis model. In this model endothelial cell spheroids were implanted in matrigel into mice, and cell growth and vessel formation were monitored in the absence and presence of inhibitor. Our study thus revealed a novel approach for therapeutic targeting of aberrant blood vessel development.
Biography

Kurt Ballmer-Hofer focused his research at PSI on the structural and functional analysis of receptor tyrosine kinases, in particular on Vascular Endothelial Growth Factor Receptors, VEGFRs. In collaboration with partner labs his team solved the structures of VEGF ligands, the ligand binding domain of VEGFR-2, and -3, and of the full-length extracellular domain of VEGFR-1 in complex with VEGF. The data of these studies led to the discovery of allosteric receptor regulatory sites in subdomains 4, 5 and 7. Antibodies and DARPins specifically binding to these domains showed strong inhibition of receptor activation and downstream signaling both in vitro and in vivo in angiogenesis model systems.

image PDF   |   image HTML
 

Relevant Topics

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

[email protected]

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

[email protected]

1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

[email protected]

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

[email protected]

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

[email protected]

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

[email protected]

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

[email protected]

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

[email protected]

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

[email protected]

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

[email protected]

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

[email protected]

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

[email protected]

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

[email protected]

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

[email protected]

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

[email protected]

1-702-714-7001 Extn: 9042

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords