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Cryo-EM of human glp-1R bound to non-peptide agonist LY3502970

Analyse Cryo-EM of human glp-1R bound to non-peptide agonist LY3502970 in the GL1X research workbench: secondary structure, accessibility, pockets, interfaces, conservation, variants, modifications, peptides, crosslinks and neighbours on the 3D structure.

PDB: 6XOX
Type: protein
Length: 1,358 residues
Chains: 6
Method: electron microscopy
Collection: MolNFT v1 / PDB
Contract: 0xDE3723766Bc32dcACD03C17BaA400A7B36837Eba
Owner: 0x3396CDB397284571d12822B4ae1189a8E22AAAAA
Molecule: Alpha subunit of gs with N-terminus swapped with equivalent residues in GI,GUANINE…
UniProt: Q5FWY2, Q5JWF2, P62873, P59768, P43220
Ligands: V6G
Pockets: 19 · best druggability 0.83

Structure

electron microscopy · 6 distinct chains · 30% helix, 27% strand (DSSP).

Chain	Molecule	Type	Residues	Secondary structure	UniProt
A	Alpha subunit of gs with N-terminus swapped with equivalent residues in GI,GUANINE nucleotide-binding protein G(S) subunit alpha isoforms xlas	protein	220	43% helix, 16% strand	Q5FWY2, Q5JWF2
B	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	protein	339	6% helix, 45% strand	P62873
E	Single-chain variable fragment SCFV16	protein	232	3% helix, 46% strand	—
G	Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2	protein	59	53% helix, 0% strand	P59768
N	Nanobody 35	protein	128	5% helix, 45% strand	—
R	Glucagon-like peptide 1 receptor	protein	380	64% helix, 3% strand	P43220

Ligands and binding sites

V6G · 3-[(1S,2S)-1-(5-[(4S)-2,2-dimethyloxan-4-yl]-2-{(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonyl}-1H-indol-1-yl)-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one · ligand · chains R

Binding sites are the residues within 4.5 Å of a ligand's heavy atoms.

Pockets

19 pockets found on a 1 Å grid, 11 with a druggability of 0.5 or more.

Pocket	Volume (Å³)	Druggability	Buriedness	Lining residues	Inside
1	659	0.83	0.87	71	empty
2	915	0.79	0.81	83	empty
3	839	0.76	0.80	71	empty
4	965	0.74	0.77	63	V6G
5	95	0.61	0.88	27	empty

Interfaces

8 interfaces between chains.

B–G · 2261 Å² buried · 15 hydrogen bonds · protein-protein
A–B · 1482 Å² buried · 24 hydrogen bonds · protein-protein
A–R · 1102 Å² buried · 13 hydrogen bonds · protein-protein
A–N · 883 Å² buried · 10 hydrogen bonds · protein-protein
B–N · 580 Å² buried · 10 hydrogen bonds · protein-protein

Modifications

Observed in the structure: 8 disulfide (disulfide).

Compared structures

6XOX · cryo-EM of human GLP-1R bound to non-peptide agonist LY3502970 · the same entry in another collection · chain R against R, TM-score 1.00
P62873 · AlphaFold monomer V2.0 prediction for guanine nucleotide-binding protein G(I)/G(S)/G(T)… · a predicted model of the same protein · chain B against A, TM-score 0.99
P59768 · AlphaFold monomer V2.0 prediction for guanine nucleotide-binding protein G(I)/G(S)/G(O)… · a predicted model of the same protein · chain G against A, TM-score 0.92
Q5JWF2 · AlphaFold monomer V2.0 prediction for guanine nucleotide-binding protein G(S) subunit… · a predicted model of the same protein · chain A against A, TM-score 0.86
P43220 · AlphaFold monomer V2.0 prediction for glucagon-like peptide 1 receptor (P43220) · a predicted model of the same protein · chain R against A, TM-score 0.84

Analyse

Open in the research workbench: secondary structure, accessibility, pockets, interfaces, conservation, variants, modifications, peptides and crosslinks on the 3D structure
Every structure of UniProt Q5FWY2
Every structure of UniProt Q5JWF2
Every structure of UniProt P62873
Every structure of UniProt P59768
Every structure of UniProt P43220
Elsewhere: RCSB PDB 6XOX · PDBe 6XOX · UniProt Q5FWY2 · UniProt Q5JWF2 · UniProt P62873 · UniProt P59768 · UniProt P43220

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