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J. Biol. Chem., Vol. 283, Issue 17, 11340-11347, April 25, 2008

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Crystal Structure of the Ligand-bound Glucagon-like Peptide-1 Receptor Extracellular Domain^*

Steffen Runge¹, Henning Thøgersen, Kjeld Madsen, Jesper Lau, and Rainer Rudolph^¶

From the Department of Structure and Biophysical Chemistry and Department of Protein and Peptide Chemistry, Novo Nordisk, 2760 Måløv, Denmark and ^¶Institute of Biotechnology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany

The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B1 of the seven-transmembrane G protein-coupled receptors, and its natural agonist ligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 is involved in glucose homeostasis, and activation of GLP-1R in the plasma membrane of pancreatic β-cells potentiates glucose-dependent insulin secretion. The N-terminal extracellular domain (nGLP-1R) is an important ligand binding domain that binds GLP-1 and the homologous peptide Exendin-4 with differential affinity. Exendin-4 has a C-terminal extension of nine amino acid residues known as the "Trp cage", which is absent in GLP-1. The Trp cage was believed to interact with nGLP-1R and thereby explain the superior affinity of Exendin-4. However, the molecular details that govern ligand binding and specificity of nGLP-1R remain undefined. Here we report the crystal structure of human nGLP-1R in complex with the antagonist Exendin-4(9–39) solved by the multiwavelength anomalous dispersion method to 2.2Å resolution. The structure reveals that Exendin-4(9–39) is an amphipathic -helix forming both hydrophobic and hydrophilic interactions with nGLP-1R. The Trp cage of Exendin-4 is not involved in binding to nGLP-1R. The hydrophobic binding site of nGLP-1R is defined by discontinuous segments including primarily a well defined -helix in the N terminus of nGLP-1R and a loop between two antiparallel β-strands. The structure provides for the first time detailed molecular insight into ligand binding of the human GLP-1 receptor, an established target for treatment of type 2 diabetes.

Received for publication, October 22, 2007 , and in revised form, January 24, 2008.

The atomic coordinates and structure factors (code 3C59) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the European Membrane Protein Consortium (E-Mep), the federal state of Saxony-Anhalt (3324 A/0021 L), and the Deutsche Forschungsgemeinshaft (SFRB 610/TP A11). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: Novo Nordisk Park G8.S.439, DK-2760 Måløv, Denmark. Tel.: 4544434431; Fax: +4544422284; E-mail: sffr{at}novonordisk.com.

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