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Cryo-EM structure of the tirzepatide (LY3298176)-bound human glp-1R-gs complex

Analyse Cryo-EM structure of the tirzepatide (LY3298176)-bound human glp-1R-gs complex in the GL1X research workbench: secondary structure, accessibility, pockets, interfaces, conservation, variants, modifications, peptides, crosslinks and neighbours on the 3D structure.

PDB: 7FIM
Type: protein
Length: 1,157 residues
Chains: 6
Method: electron microscopy
Collection: MolNFT v1 / PDB
Contract: 0xDE3723766Bc32dcACD03C17BaA400A7B36837Eba
Owner: 0x3396CDB397284571d12822B4ae1189a8E22AAAAA
Molecule: Nanobody-35; Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1; Guanine…
UniProt: P54311, P04896, P43220, P63212
Pockets: 12 · best druggability 0.79

Structure

electron microscopy · 6 distinct chains · 36% helix, 20% strand (DSSP).

Chain	Molecule	Type	Residues	Secondary structure	UniProt
N	Nanobody-35	protein	126	5% helix, 37% strand	—
B	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	protein	337	8% helix, 43% strand	P54311
A	Guanine nucleotide-binding protein G(S) subunit alpha isoforms short	protein	226	46% helix, 15% strand	P04896
R	Glucagon-like peptide 1 RECEPTOR,GLUCAGON-like peptide 1 RECEPTOR,GLUCAGON-like peptide 1 RECEPTOR,GLUCAGON-like peptide 1 RECEPTOR,HUMAN glucagon like peptide 1 receptor	protein	382	60% helix, 3% strand	P43220
G	Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2	protein	57	53% helix, 0% strand	P63212
P	Tirzepatide	protein	29	93% helix, 0% strand	—

Pockets

12 pockets found on a 1 Å grid, 6 with a druggability of 0.5 or more.

Pocket	Volume (Å³)	Druggability	Buriedness	Lining residues	Inside
1	676	0.79	0.84	52	empty
2	991	0.74	0.77	64	empty
3	805	0.73	0.78	73	empty
4	126	0.72	0.93	22	empty
5	692	0.72	0.79	75	empty

Interfaces

7 interfaces between chains.

B–G · 2105 Å² buried · 14 hydrogen bonds · protein-protein
R–P · 1730 Å² buried · 4 hydrogen bonds · protein-protein
B–A · 1422 Å² buried · 15 hydrogen bonds · protein-protein
A–R · 1022 Å² buried · 15 hydrogen bonds · protein-protein
N–A · 798 Å² buried · 12 hydrogen bonds · protein-protein

Modifications

Observed in the structure: 6 disulfide, 2 modified (disulfide, nonstandard).

Compared structures

7FIM · Cryo-EM structure of the tirzepatide (LY3298176)-bound human GLP-1R-Gs complex · the same entry in another collection · chain P against P, TM-score 1.00
P54311 · 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
P04896 · 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 0.84
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 0.78
P63212 · 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 0.65

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 P54311
Every structure of UniProt P04896
Every structure of UniProt P43220
Every structure of UniProt P63212
Elsewhere: RCSB PDB 7FIM · PDBe 7FIM · UniProt P54311 · UniProt P04896 · UniProt P43220 · UniProt P63212

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