8YW5: Retatrutide-bound human GCGR-Gs complex

Cryo-EM structure of the retatrutide-bound human GCGR-Gs complex. Determined by electron microscopy at 2.84 Å resolution. Released 7 Aug 2024.

Method: Electron microscopy
Resolution: 2.84 Å
Organisms: Homo sapiens, synthetic construct
Chains: 6
Atoms: 8,937
Mol. weight: 156.9 kDa
Released: 7 Aug 2024

Explore 8YW5 in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

8YW5 contains 36 α-helices and 49 β-strands across 6 chains. Residue ranges use author residue numbering, as in the PDB file, from PDBe. To see them in 3D, choose the Cartoon representation with Secondary structure coloring: helices, sheets and coils get different colors.

Chain A: 8 helices, 6 β-strands

Element	Residues	Length	Sheet
α-helix	10-38	29
β-strand	40-47	8	3
α-helix	53-55	3
β-strand	210-214	5	3
β-strand	217-223	7	3
α-helix	234-238	5
β-strand	243-249	7	3
α-helix	265-278	14
β-strand	286-292	7	3
α-helix	294-303	10
α-helix	315-317	3
α-helix	332-350	19
β-strand	359-362	4	3
α-helix	371-390	20

Chain B: 3 helices, 28 β-strands

Element	Residues	Length	Sheet
α-helix	4-25	22
α-helix	30-33	4
β-strand	47-51	5	4
β-strand	58-63	6	5
β-strand	69-74	6	5
β-strand	78-83	6	5
β-strand	88-94	7	5
β-strand	100-105	6	6
β-strand	111-116	6	6
β-strand	121-125	5	6
β-strand	134-139	6	6
β-strand	146-151	6	7
β-strand	156-161	6	7
β-strand	165-170	6	7
β-strand	175-181	7	7
β-strand	187-192	6	8
β-strand	198-203	6	8
β-strand	207-212	6	8
β-strand	218-223	6	8
β-strand	229-234	6	9
β-strand	240-245	6	9
β-strand	250-254	5	9
β-strand	259-264	6	9
α-helix	272	1
β-strand	273-277	5	10
β-strand	284-289	6	10
β-strand	294-298	5	10
β-strand	303-308	6	10
β-strand	315-320	6	4
β-strand	327-331	5	4
β-strand	336-339	4	4

Chain G: 4 helices, 0 β-strands

Element	Residues	Length
α-helix	8-23	16
α-helix	30-43	14
α-helix	53-55	3
α-helix	56-58	3

Chain N: 2 helices, 11 β-strands

Element	Residues	Length	Sheet
β-strand	3-7	5	11
β-strand	10-12	3	12
β-strand	17-25	9	11
α-helix	29-31	3
β-strand	34-39	6	12
β-strand	46-51	6	12
β-strand	58-60	3	12
β-strand	69-73	5	11
β-strand	78-84	7	11
α-helix	88-90	3
β-strand	92-98	7	12
β-strand	118	1	12
β-strand	122-126	5	12

Chain P: 1 helix, 0 β-strands

Element	Residues	Length	Sheet
α-helix	2-27	26

Chain R: 18 helices, 4 β-strands

Element	Residues	Length	Sheet
α-helix	29-46	18
β-strand	61-62	2	1
β-strand	67-68	2	1
β-strand	79-80	2	2
α-helix	81-82	2
β-strand	95-96	2	2
α-helix	123-124	2
α-helix	125-163	39
α-helix	172-202	31
α-helix	209-216	8
α-helix	222-252	31
α-helix	266-268	3
α-helix	269-273	5
α-helix	276-289	14
α-helix	301-304	4
α-helix	309-333	25
α-helix	344-350	7
α-helix	354-358	5
α-helix	362-365	4
α-helix	381-397	17
α-helix	398-402	5
α-helix	405-418	14

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Retatrutide	P	protein	30	Homo sapiens
Glucagon receptor	R	protein	406	Homo sapiens	P47871 (AlphaFold model)
Guanine nucleotide-binding protein G(s) subunit alpha isoforms short	A	protein	394	Homo sapiens	P63092 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	B	protein	345	Homo sapiens	P62873 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2	G	protein	71	Homo sapiens	P59768 (AlphaFold model)
Nanobody-35	N	protein	140	synthetic construct

Sequence of entity 1 (P), FASTA

>8YW5_1 Retatrutide (chains P)
YAQGTFTSDYSILLDKKAQAAFIEYLLEGG

Sequence of entity 2 (R), FASTA

>8YW5_2 Glucagon receptor (chains R)
QVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLP
WHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQVMYT
VGYSLSLGALLLALAILGGLSKLHCTRNAIHANLFASFVLKASSVLVIDGLLRTRYSQKI
GDDLSVSTWLSDGAVAGCRVAAVFMQYGIVANYCWLLVEGLYLHNLLGLATLPERSFFSL
YLGIGWGAPMLFVVPWAVVKCLFENVQCWTSNDNMGFWWILRFPVFLAILINFFIFVRIV
QLLVAKLRARQMHHTDYKFRLAKSTLTLIPLLGVHEVVFAFVTDEHAQGTLRSAKLFFDL
FLSSFQGLLVAVLYCFLNKEVQSELRRRWHRWRLGKVLWEERNTSN

Sequence of entity 3 (A), FASTA

>8YW5_3 Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (chains A)
MGCLGNSKTEDQRNEEKAQREANKKIEKQLQKDKQVYRATHRLLLLGAGESGKNTIVKQM
RILHVNGFNGEGGEEDPQAARSNSDGEKATKVQDIKNNLKEAIETIVAAMSNLVPPVELA
NPENQFRVDYILSVMNVPDFDFPPEFYEHAKALWEDEGVRACYERSNEYQLIDCAQYFLD
KIDVIKQADYVPSDQDLLRCRVLTSGIFETKFQVDKVNFHMFDVGAQRDERRKWIQCFND
VTAIIFVVASSSYNMVIREDNQTNRLQAALKLFDSIWNNKWLRDTSVILFLNKQDLLAEK
VLAGKSKIEDYFPEFARYTTPEDATPEPGEDPRVTRAKYFIRDEFLRISTASGDGRHYCY
PHFTCAVDTENIRRVFNDCRDIIQRMHLRQYELL

Sequence of entity 4 (B), FASTA

>8YW5_4 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 (chains B)
MGSLLQSELDQLRQEAEQLKNQIRDARKACADATLSQITNNIDPVGRIQMRTRRTLRGHL
AKIYAMHWGTDSRLLVSASQDGKLIIWDSYTTNKVHAIPLRSSWVMTCAYAPSGNYVACG
GLDNICSIYNLKTREGNVRVSRELAGHTGYLSCCRFLDDNQIVTSSGDTTCALWDIETGQ
QTTTFTGHTGDVMSLSLAPDTRLFVSGACDASAKLWDVREGMCRQTFTGHESDINAICFF
PNGNAFATGSDDATCRLFDLRADQELMTYSHDNIICGITSVSFSKSGRLLLAGYDDFNCN
VWDALKADRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLKIWN

Sequence of entity 5 (G), FASTA

>8YW5_5 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (chains G)
MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP
FREKKFFCAIL

Sequence of entity 6 (N), FASTA

>8YW5_6 Nanobody-35 (chains N)
MAQVQLQESGGGLVQPGGSLRLSCAASGFTFSNYKMNWVRQAPGKGLEWVSDISQSGASI
SYTGSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCARCPAPFTRDCFDVTSTTYAYR
GQGTQVTVSSHHHHHHEPEA

Primary citation

Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide. Li, W., Zhou, Q., Cong, Z. et al. Cell Discov (2024) 10:77-77. DOI 10.1038/s41421-024-00700-0 · PubMed

Other PDB entries of the same protein (UniProt P47871 (AlphaFold model), which also has an AlphaFold model), best resolution first:

3CZF 1.2 Å, Crystal structure of HLA-B*2709 complexed with the glucagon receptor (GR) peptide…
2A83 1.4 Å, Crystal structure of hla-b*2705 complexed with the glucagon receptor (gr) peptide…
9N04 2.3 Å, Cryo-EM structure of GCGR-Gs complex with peptide 15
9N0E 2.3 Å, Cryo-EM structure of GCGR-Gs complex with oxyntomodulin
5EE7 2.5 Å, Crystal structure of the human glucagon receptor (GCGR) in complex with the antagonist…
9XN4 2.53 Å, Glucagon receptor-Gs complex activated by the small molecule agonist SIM1
4ERS 2.64 Å, A Molecular Basis for Negative Regulation of the Glucagon Receptor
8WG8 2.71 Å, Cryo-EM structures of peptide free and Gs-coupled GCGR
4LF3 2.73 Å, Inhibitory Mechanism of an Allosteric Antibody Targeting the Glucagon Receptor
8JIU 2.76 Å, Cryo-EM structure of the GLP-1R/GCGR dual agonist SAR425899-bound human GCGR-Gs complex
8FU6 2.9 Å, GCGR-Gs complex in the presence of RAMP2
8JIT 2.91 Å, Cryo-EM structure of the GLP-1R/GCGR dual agonist MEDI0382-bound human GCGR-Gs complex

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