Structure of Human Urokinase Plasminogen Activator in Complex with Its Receptor

doi:10.1126/science.1121143

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Structure of Human Urokinase Plasminogen Activator in Complex with Its Receptor

Qing Huai,¹ Andrew P. Mazar,² Alice Kuo,³ Graham C. Parry,² David E. Shaw,⁶ Jennifer Callahan,² Yongdong Li,⁴ Cai Yuan,⁴ Chuanbing Bian,⁴ Liqing Chen,⁵ Bruce Furie,¹ Barbara C. Furie,¹ Douglas B. Cines,³ Mingdong Huang¹^,4^*

Abstract: The urokinase plasminogen activator binds to its cellular receptorwith high affinity and initiates signaling cascades that areimplicated in pathological processes including tumor growth,metastasis, and inflammation. We report the crystal structureat 1.9 angstroms of the urokinase receptor complexed with theurokinase amino-terminal fragment and an antibody against thereceptor. The three domains of urokinase receptor form a concaveshape with a central cone-shaped cavity where the urokinasefragment inserts. The structure provides insight into the flexibilityof the urokinase receptor that enables its interaction witha wide variety of ligands and a basis for the design of urokinase-urokinasereceptor antagonists.

¹ Division of Hemostasis and Thrombosis, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
² Attenuon, LLC, 11535 Sorrento Valley Road, Suite 401, San Diego, CA 92121, USA.
³ Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 513A Stellar-Chance, 422 Curie Boulevard, Philadelphia, PA 19104, USA.
⁴ State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, People's Republic of China.
⁵ Laboratory for Structural Biology, Department of Chemistry, Graduate Programs of Biotechnology, Chemistry and Materials Science, University of Alabama in Huntsville, Huntsville, AL 35899, USA.
⁶ D. E. Shaw Research and Development, 39th Floor, Tower 45, 120 West Forty-Fifth Street, New York, NY 10036, USA.

^* To whom correspondence should be addressed. E-mail: mhuang1{at}bidmc.harvard.edu, mhuang{at}fjirsm.ac.cn

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