8YW4: Retatrutide-bound human GIPR-Gs complex

Cryo-EM structure of the retatrutide-bound human GIPR-Gs complex. Determined by electron microscopy at 3.26 Å resolution. Released 18 Sept 2024.

Method: Electron microscopy
Resolution: 3.26 Å
Organisms: Homo sapiens, synthetic construct
Chains: 6
Atoms: 8,619
Mol. weight: 170.81 kDa
Released: 18 Sept 2024

Explore 8YW4 in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

8YW4 contains 34 α-helices and 53 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: 9 helices, 7 β-strands

Element	Residues	Length	Sheet
α-helix	6-32	27
β-strand	34-39	6	1
α-helix	46-53	8
β-strand	184-191	8	1
β-strand	194-201	8	1
α-helix	212-215	4
β-strand	220-226	7	1
α-helix	233-245	13
β-strand	253-259	7	1
α-helix	261-270	10
α-helix	275-277	3
α-helix	293-294	2
α-helix	299-319	21
β-strand	326	1	1
β-strand	329-330	2	1
α-helix	339-357	19

Chain B: 4 helices, 30 β-strands

Element	Residues	Length	Sheet
α-helix	4-24	21
α-helix	30-33	4
α-helix	38-39	2
β-strand	46-51	6	2
β-strand	58-62	5	3
β-strand	71-74	4	3
β-strand	78-81	4	3
β-strand	91-94	4	3
α-helix	95	1
β-strand	104-105	2	4
β-strand	111-113	3	4
β-strand	120-125	6	4
β-strand	134-140	7	4
β-strand	146-150	5	5
β-strand	156-161	6	5
β-strand	165-170	6	5
β-strand	175-181	7	5
β-strand	187-192	6	6
β-strand	198-203	6	6
β-strand	208-212	5	6
β-strand	218-222	5	6
β-strand	229-232	4	7
β-strand	240-245	6	7
β-strand	250-254	5	7
β-strand	259-264	6	7
β-strand	273-278	6	8
β-strand	284-289	6	8
β-strand	294-298	5	8
β-strand	306-308	3	8
β-strand	315	1	9
β-strand	319-320	2	2
β-strand	327-329	3	2
β-strand	331	1	9
β-strand	336-340	5	2

Chain G: 4 helices, 0 β-strands

Element	Residues	Length
α-helix	7-23	17
α-helix	30-43	14
α-helix	45-47	3
α-helix	54-55	2

Chain N: 2 helices, 16 β-strands

Element	Residues	Length	Sheet
β-strand	3	1	10
β-strand	6	1	11
β-strand	10-12	3	12
β-strand	17-23	7	11
β-strand	25	1	10
β-strand	34-35	2	13
β-strand	38-39	2	12
β-strand	45-46	2	12
β-strand	49-51	3	13
β-strand	58-60	3	13
α-helix	62-64	3
β-strand	69-73	5	11
β-strand	78-84	7	11
α-helix	88-90	3
β-strand	92-94	3	12
β-strand	97-98	2	13
β-strand	118	1	13
β-strand	122-126	5	12

Chain P: 1 helix, 0 β-strands

Element	Residues	Length	Sheet
α-helix	2-26	25

Chain R: 14 helices, 0 β-strands

Element	Residues	Length
α-helix	32-47	16
α-helix	129-160	32
α-helix	168-193	26
α-helix	197-200	4
α-helix	213-245	33
α-helix	256-260	5
α-helix	261-265	5
α-helix	266-281	16
α-helix	293-296	4
α-helix	300-327	28
α-helix	335-350	16
α-helix	352-357	6
α-helix	368-391	24
α-helix	397-410	14

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Mini-Gs	A	protein	361	Homo sapiens	P63092 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	B	protein	341	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
Gastric inhibitory polypeptide receptor	R	protein	573	Homo sapiens	P48546 (AlphaFold model)
retatrutide	P	protein	27	Homo sapiens

Sequence of entity 1 (A), FASTA

>8YW4_1 Mini-Gs (chains A)
MGCTLSAEDKAAVERSKMIEKQLQKDKQVYRATHRLLLLGADNSGKSTIVKQMRIYHVNG
YSEEECKQYKAVVYSNTIQSIIAIIRAMGRLKIDFGDSARADDARQLFVLAGAAEEGFMT
AELAGVIKRLWKDSGVQACFNRSREYQLNDSAAYYLNDLDRIAQPNYIPTQQDVLRTRVK
TSGIFETKFQVDKVNFHMFDVGAQRDERRKWIQCFNDVTAIIFVVDSSDYNRLQEALNDF
KSIWNNRWLRTISVILFLNKQDLLAEKVLAGKSKIEDYFPEFARYTTPEDATPEPGEDPR
VTRAKYFIRDEFLRISTASGDGRHYCYPHFTCSVDTENARRIFNDCRDIIQRMHLRQYEL
L

Sequence of entity 2 (B), FASTA

>8YW4_2 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 (chains B)
ELDQLRQEAEQLKNQIRDARKACADATLSQITNNIDPVGRIQMRTRRTLRGHLAKIYAMH
WGTDSRLLVSASQDGKLIIWDSYTTNKVHAIPLRSSWVMTCAYAPSGNYVACGGLDNICS
IYNLKTREGNVRVSRELAGHTGYLSCCRFLDDNQIVTSSGDTTCALWDIETGQQTTTFTG
HTGDVMSLSLAPDTRLFVSGACDASAKLWDVREGMCRQTFTGHESDINAICFFPNGNAFA
TGSDDATCRLFDLRADQELMTYSHDNIICGITSVSFSKSGRLLLAGYDDFNCNVWDALKA
DRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLKIWNGSS

Sequence of entity 3 (G), FASTA

>8YW4_3 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (chains G)
MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP
FREKKFFCAIL

Sequence of entity 4 (N), FASTA

>8YW4_4 Nanobody-35 (chains N)
MAQVQLQESGGGLVQPGGSLRLSCAASGFTFSNYKMNWVRQAPGKGLEWVSDISQSGASI
SYTGSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCARCPAPFTRDCFDVTSTTYAYR
GQGTQVTVSSHHHHHHEPEA

Sequence of entity 5 (R), FASTA

>8YW4_5 Gastric inhibitory polypeptide receptor (chains R)
RAETGSKGQTAGELYQRWERYRRECQETLAAAEPPSGLACNGSFDMYVCWDYAAPNATAR
ASCPWYLPWHHHVTAGFELYQCGSDGRWERYRDHTQCENRECQEAFLDQRLILERLQVMY
TVGYSLSLATLLLALLILSLFRRLHCTRNYIHINLFTSFMLRAAAILSRDRLLPRPGPYL
GDQALALWNQALAACRTAQIVTQYCVGANYTWLLVEGVYLHSLLVLVGGSEEGHFRYYLL
LGWGAPALFVIPWVIVRYLYENTQCWERNEVKAIWWIIRTPILMTILINFLIFIRILGIL
LSKLRTRQMRCRDYRLRLARSTLFLVPLLGVHEVVFAPVTEEQARGALRFAKLGFEIFLS
SFQGFLVSVLYCFINKEVQSEIRRGWHHCRLRRSLGEEQRGSSGGGGSGGGGSSGVFTLE
DFVGDWEQTAAYNLDQVLEQGGVSSLLQNLAVSVTPIQRIVRSGENALKIDIHVIIPYEG
LSADQMAQIEEVFKVVYPVDDHHFKVILPYGTLVIDGVTPNMLNYFGRPYEGIAVFDGKK
ITVTGTLWNGNKIIDERLITPDGSMLFRVTINS

Sequence of entity 6 (P), FASTA

>8YW4_6 retatrutide (chains P)
YAQGTFTSDYSILLDKKAQAAFIEYLL

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 P63092 (AlphaFold model), which also has an AlphaFold model), best resolution first:

7BPH 1.57 Å, Crystal structure of GppNHp-bound GNAS in complex with the cyclic peptide inhibitor GN13
6AU6 1.7 Å, Crystal structure of GDP-bound human GNAS R201C mutant
8F0K 1.9 Å, Human Amylin3 Receptor in complex with Gs and Pramlintide analogue peptide San385
7E5E 1.95 Å, Crystal structure of GDP-bound GNAS in complex with the cyclic peptide inhibitor GD20
7MBX 1.95 Å, Human Cholecystokinin 1 receptor (CCK1R) Gs complex
8F0J 2.0 Å, Calcitonin Receptor in complex with Gs and Pramlintide analogue peptide San45
8F2B 2.0 Å, Amylin 3 Receptor in complex with Gs and Pramlintide analogue peptide San45
9XXT 2.0 Å, Cryo-EM structure of lysophosphatidylserine (18:0)-bound GPR174-Gs complex
6X18 2.1 Å, GLP-1 peptide hormone bound to Glucagon-Like peptide-1 (GLP-1) Receptor
6X19 2.1 Å, Non peptide agonist CHU-128, bound to Glucagon-Like peptide-1 (GLP-1) Receptor
9NTU 2.1 Å, Cryo-EM structure of BETP-GLP-1(9-36)-GLP-1R-Gs complex
7RTB 2.14 Å, Peptide-19 bound to the Glucagon-Like Peptide-1 Receptor (GLP-1R)

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