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PNAS 109 (31): 12491-12496

Copyright © 2012 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor

Xuliang Jianga, Heli Liub, Xiaoyan Chenb, Po-Han Chenb, David Fischera, Venkataraman Sriramana, Henry N. Yua, Steve Arkinstalla, and Xiaolin Heb,1

a EMD Serono Research Institute, Billerica, MA 01821; and bDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL 60611

Edited by Wayne A. Hendrickson, Columbia University, New York, NY, and approved June 22, 2012 (received for review April 25, 2012)

Abstract: FSH, a glycoprotein hormone, and the FSH receptor (FSHR), a G protein-coupled receptor, play central roles in human reproduction. We report the crystal structure of FSH in complex with the entire extracellular domain of FSHR (FSHRED), including the enigmatic hinge region that is responsible for signal specificity. Surprisingly, the hinge region does not form a separate structural unit as widely anticipated but is part of the integral structure of FSHRED. In addition to the known hormone-binding site, FSHRED provides interaction sites with the hormone: a sulfotyrosine (sTyr) site in the hinge region consistent with previous studies and a potential exosite resulting from putative receptor trimerization. Our structure, in comparison to others, suggests FSHR interacts with its ligand in two steps: ligand recruitment followed by sTyr recognition. FSH first binds to the high-affinity hormone-binding subdomain of FSHR and reshapes the ligand conformation to form a sTyr-binding pocket. FSHR then inserts its sTyr (i.e., sulfated Tyr335) into the FSH nascent pocket, eventually leading to receptor activation.

Key Words: sulfated tyrosine recognition • signal transduction • reproductive hormone • leucine-rich repeat • CF3 motif

Author contributions: X.J. and X.H. designed research; X.J., H.L., X.C., P.-H.C., D.F., V.S., H.N.Y., and X.H. performed research; X.J., S.A., and X.H. analyzed data; and X.J. and X.H. wrote the paper.

Conflict of interest statement: D.F., V.S., H.N.Y., S.A., and X.J. are employees of EMD Serono, Inc., an affiliate of Merck KGaA, Germany, whose commercial products include FSH.

This article is a PNAS Direct Submission.

Data deposition: The atomic coordinates and structural factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 4AY9).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1206643109/-/DCSupplemental.

1To whom correspondence should be addressed. E-mail: x-he{at}northwestern.edu.

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