Glucagon-like peptide 1 receptor: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<StructureSection load='3iol' size='350' side='right' scene='84/841095/Cv/1' caption='Human GLP-1R extracellular domain (deepskyblue) complex with GLP-1 peptide (green) and a pyranose derivative (PDB code [[3iol]])'>
<StructureSection load='3iol' size='350' side='right' scene='84/841095/Cv/1' caption='Human GLP-1R extracellular domain (deepskyblue) complex with GLP-1 peptide (green) and a pyranose derivative (PDB code [[3iol]])'>Human GLP-1R has 463 amino acids. It is comprised of an extracellular hydrophilic N-terminal domain, seven hydrophobic transmembrane alpha-helices, three hydrophilic extracellular loops, three intracellular loops, and an intracellular C-terminal domain interacting with G-proteins.  
 
Human GLP-1R has 463 amino acids. It is comprised of an extracellular hydrophilic N-terminal domain, seven hydrophobic transmembrane alpha-helices, three hydrophilic extracellular loops, three intracellular loops, and an intracellular C-terminal domain interacting with G-proteins.  


The 3D crystal structure of the complex of GLP-1R (extra-cellular domain only) and GLP-1 shows the GLP-1 peptide as a kinked helix. The ampiphilic GLP-1 helix shows <scene name='84/841095/Cv/2'>hydrophilic</scene> and <scene name='84/841095/Cv/3'>hydrophobic</scene> interactions with GLP-1R on opposite faces<ref>PMID:19861722</ref>. <scene name='84/841095/Cv/5'>GLP-1R/GLP-1 salt bridges and H-bonds</scene>.
The 3D crystal structure of the complex of GLP-1R (extra-cellular domain only) and GLP-1 shows the GLP-1 peptide as a kinked helix. The ampiphilic GLP-1 helix shows <scene name='84/841095/Cv/2'>hydrophilic</scene> and <scene name='84/841095/Cv/3'>hydrophobic</scene> interactions with GLP-1R on opposite faces<ref>PMID:19861722</ref>. <scene name='84/841095/Cv/5'>GLP-1R/GLP-1 salt bridges and H-bonds</scene>.


More recently, the structure of <scene name='10/1067195/Glp1_only/1'>full-length GLP-1R</scene> was determined by cryo-EM, with or without bound agonist.  
More recently, the structure of <scene name='84/841095/Glp1r_overview/1'>full-length GLP-1R</scene> was determined by cryo-EM, with or without bound agonist.  


In regard to GLP-1R, GLP-1 is an agonist with very high binding affinity, in the nanomolar range, and changes to the specified residues can greatly impact binding affinity. As evidenced by the glucagon receptor, there are differences in the peptide-free and peptide-bound states with the most significant structural differences observed in the extracellular regions. The same applies to GLP-1 Receptor, with GLP-1 bound GLP-1R having an extended ECD as compared to the unbound GLP-1R. A large degree of conformational dynamics is critical for the binding of GLP-1. The N-terminus triggers a conformational change that results in G-protein coupling and activation of downstream signaling, while the C-terminus of the peptide initiates recognition of the ECD. There is a notable β-sheet motif when the GLP-1R has no bound peptide. This sheet is seen in the ECD which is important for the GLP-1 recognition and the conformational dynamic changes in the receptor when it is bound to a peptide versus when it is not.
In regard to GLP-1R, GLP-1 is an agonist with very high binding affinity, in the nanomolar range, and changes to the specified residues can greatly impact binding affinity. As evidenced by the glucagon receptor, there are differences in the peptide-free and peptide-bound states with the most significant structural differences observed in the extracellular regions. The same applies to GLP-1 Receptor, with GLP-1 bound GLP-1R having an extended ECD as compared to the unbound GLP-1R.  


[[Image:Image:GLP1R conformations.png|300px]]
A large degree of conformational dynamics is critical for the binding of GLP-1. The N-terminus triggers a conformational change that results in G-protein coupling and activation of downstream signaling, while the C-terminus of the peptide initiates recognition of the ECD. There is a notable β-sheet motif when the GLP-1R has no bound peptide. This sheet is seen in the ECD which is important for the GLP-1 recognition and the conformational dynamic changes in the receptor when it is bound to a peptide versus when it is not. The figure shows two pathways to bind GLP-1. On the top, GLP-1 binds to the ECD first, and then undergoes conformational change to allow binding to the transmembrane portion. On the bottom, GLP-1 binds to the transmembrane portion first at times when the empty receptor is in the open state, followed by binding of the ECD.


[[Image:GLP1R.gif|Morph between the open and closed conformation of the extra-cellular domain (yellow). In the closed form, GLP-1 (green) clashes with the domain]]


</StructureSection>
</StructureSection>

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Michal Harel, Alexander Berchansky, Karsten Theis
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