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  • The EMBO Journal (2007) 26, 4902 - 4912
  • doi:10.1038/sj.emboj.7601906

Published online: 8 November 2007

Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding

Brent A Appleton1, Ping Wu1, Janice Maloney2, JianPing Yin1, Wei-Ching Liang3, Scott Stawicki3, Kyle Mortara1, Krista K Bowman1, J Michael Elliott4, William Desmarais1,a, J Fernando Bazan1, Anil Bagri2, Marc Tessier-Lavigne5, Alexander W Koch4, Yan Wu3, Ryan J Watts2 and Christian Wiesmann1

  1. Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA
  2. Department of Tumor Biology & Angiogenesis, Genentech, Inc., South San Francisco, CA, USA
  3. Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA
  4. Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA, USA
  5. Department of Research Drug Discovery, Genentech, Inc., South San Francisco, CA, USA

Correspondence to:

Christian Wiesmann, Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Tel.: +1 650 225 7484; Fax: +1 650 225 3734; E-mail: chw@gene.com

aPresent address: Lilly Corporate Center, Indianapolis, IN 46285, USA

Received 28 June 2007; Accepted 8 October 2007

Neuropilins (Nrps) are co-receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with in vitro experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.

  • Keywords:

    • neuropilin,
    • neuroscience,
    • tumorigenesis,
    • vasculogenesis,
    • X-ray crystallography