Structural aspects of urokinase receptor in vascular biology

Summary

Principal Investigator: Mingdong Huang
Affiliation: Harvard University
Country: USA
Abstract: DESCRIPTION (provided by applicant): Urokinase plasminogen activator (uPA) together with its cell surface receptor (uPAR) mediates surface-bound plasminogen activation and has been recognized to play essential roles in several biological processes important in vascular biology, including clot lysis, cell adhesion, cell migration, inflammation, signal transduction, angiogenesis, and chemotaxis. Therefore, the study of this system will be critical to understand the causes, prevention, and treatment of vascular disorders and diseases including tumor invasion, tumor metastasis, neointima formation, infection with human immunodeficiency virus-1 (HIV-1), Alzheimer disease, and multiple sclerosis. The molecular basis for these broad physiological and pathophysiological roles of uPAR/uPA system stems from uPAR's capability to interact with many diverse ligands, e.g., uPA, vitronectin, integrins (31, 32, 33), LRP, GPCR, and the dynamic conformational changes caused by these protein-protein interactions. The principal investigator's recent results (Huai, et al. "Structure of Human Urokinase Plasminogen Activator in Complex", Science, in press, 2006) suggest conformational flexibility of uPAR. The goal of this proposal is to systematically study the structural basis and the dynamic nature of the interactions between uPAR and its ligands. The principal investigator proposes to study the structures of soluble uPAR (suPAR) (aim 1), suPAR in complex with vitronectin (aim 2), suPAR in complex with full- length uPA (aim 3), and to compare and analyze the structures of suPAR and suPAR-ligand complexes (aim 4). Protein X-ray crystallography will be the main tool to study these protein-protein interactions, but other common molecular and cell biology techniques will also be used. The principal investigator has established methods to generate needed reagents and has made several preliminary suPAR-ligand crystals, providing a solid basis for these proposed studies. These systematic structural studies of uPAR and its complexes with physiologically important uPA forms and vitronectin will understand the dynamic interactions between uPAR and its ligands, identify unanimously the binding determinants on the receptor and the ligands that confer therapeutic accessibility, and provide a framework for future design and optimization of small molecular antagonists to regulate these protein-protein interactions and to intervene the pathologic consequences resulting from these interactions.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Structure of human urokinase plasminogen activator in complex with its receptor
    Qing Huai
    Division of Hemostasis and Thrombosis, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
    Science 311:656-9. 2006
  2. pmc Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes
    Qing Huai
    Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
    Nat Struct Mol Biol 15:422-3. 2008
  3. pmc Structure-based engineering of species selectivity in the interaction between urokinase and its receptor: implication for preclinical cancer therapy
    Lin Lin
    Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 285:10982-92. 2010
  4. pmc Challenges for drug discovery - a case study of urokinase receptor inhibition
    Zhuo Chen
    State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
    Comb Chem High Throughput Screen 12:961-7. 2009
  5. pmc Trp2313-His2315 of factor VIII C2 domain is involved in membrane binding: structure of a complex between the C2 domain and an inhibitor of membrane binding
    Zhuo Liu
    State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China
    J Biol Chem 285:8824-9. 2010
  6. ncbi Structural basis for therapeutic intervention of uPA/uPAR system
    Jacky Chi Ki Ngo
    The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
    Curr Drug Targets 12:1729-43. 2011
  7. doi Crystal structure of the urokinase receptor in a ligand-free form
    Xiang Xu
    Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
    J Mol Biol 416:629-41. 2012

Detail Information

Publications7

  1. ncbi Structure of human urokinase plasminogen activator in complex with its receptor
    Qing Huai
    Division of Hemostasis and Thrombosis, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
    Science 311:656-9. 2006
    ..The structure provides insight into the flexibility of the urokinase receptor that enables its interaction with a wide variety of ligands and a basis for the design of urokinase-urokinase receptor antagonists...
  2. pmc Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes
    Qing Huai
    Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
    Nat Struct Mol Biol 15:422-3. 2008
    ..These results provide a structural understanding of one receptor binding to two ligands...
  3. pmc Structure-based engineering of species selectivity in the interaction between urokinase and its receptor: implication for preclinical cancer therapy
    Lin Lin
    Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 285:10982-92. 2010
    ..uPAR interaction, which is highly relevant for functional studies in mouse models, but it also suggests the possible development of general inhibitors that will target the uPA.uPAR interaction across species barriers...
  4. pmc Challenges for drug discovery - a case study of urokinase receptor inhibition
    Zhuo Chen
    State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
    Comb Chem High Throughput Screen 12:961-7. 2009
    ....
  5. pmc Trp2313-His2315 of factor VIII C2 domain is involved in membrane binding: structure of a complex between the C2 domain and an inhibitor of membrane binding
    Zhuo Liu
    State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China
    J Biol Chem 285:8824-9. 2010
    ..This result indicates that the Trp(2313)-His(2315) segment is an important constituent of the membrane-binding motif and provides a model to understand the molecular mechanism of the C2 domain membrane interaction...
  6. ncbi Structural basis for therapeutic intervention of uPA/uPAR system
    Jacky Chi Ki Ngo
    The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
    Curr Drug Targets 12:1729-43. 2011
    ..Recent progress on uPA inhibitors will be summarized in this article. The unique structural features and the druggable potentials of these new structures will also be discussed...
  7. doi Crystal structure of the urokinase receptor in a ligand-free form
    Xiang Xu
    Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
    J Mol Biol 416:629-41. 2012
    ..Together, these studies provide new insights into uPAR structure-function relationships, emphasizing the importance of the inter-domain dynamics of this modular receptor...