7FIY: Tirzepatide-bound human GIPR-Gs complex

Cryo-EM structure of the tirzepatide-bound human GIPR-Gs complex. Determined by electron microscopy at 3.4 Å resolution. Released 2 Mar 2022.

Method: Electron microscopy
Resolution: 3.4 Å
Organisms: Homo sapiens, synthetic construct, Bos taurus
Chains: 6
Atoms: 9,367
Mol. weight: 180.52 kDa
Ligands: CLR
Released: 2 Mar 2022

Explore 7FIY in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

7FIY contains 33 α-helices and 52 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, 6 β-strands

Element	Residues	Length	Sheet
α-helix	10-39	30
β-strand	41-45	5	4
α-helix	53-59	7
β-strand	207-213	7	4
β-strand	218-224	7	4
α-helix	234-238	5
β-strand	243-249	7	4
α-helix	267-277	11
β-strand	286-292	7	4
α-helix	294-303	10
α-helix	307-311	5
α-helix	325-327	3
α-helix	332-352	21
β-strand	359-363	5	4
α-helix	370-390	21

Chain B: 3 helices, 28 β-strands

Element	Residues	Length	Sheet
α-helix	5-24	20
α-helix	30-33	4
β-strand	45-51	7	5
β-strand	58-63	6	6
β-strand	69-74	6	6
β-strand	78-83	6	6
β-strand	88-94	7	6
β-strand	100-105	6	7
β-strand	111-116	6	7
β-strand	121-125	5	7
β-strand	134-139	6	7
α-helix	145	1
β-strand	146-151	6	8
β-strand	156-161	6	8
β-strand	166-170	5	8
β-strand	176-180	5	8
β-strand	187-192	6	9
β-strand	198-203	6	9
β-strand	208-212	5	9
β-strand	218-222	5	9
β-strand	229-234	6	10
β-strand	240-245	6	10
β-strand	250-254	5	10
β-strand	259-264	6	10
β-strand	273-278	6	11
β-strand	284-289	6	11
β-strand	294-298	5	11
β-strand	304-308	5	11
β-strand	315-320	6	5
β-strand	327-331	5	5
β-strand	336-341	6	5

Chain G: 2 helices, 0 β-strands

Element	Residues	Length	Sheet
α-helix	7-23	17
α-helix	30-43	14

Chain N: 3 helices, 11 β-strands

Element	Residues	Length	Sheet
β-strand	3-7	5	12
β-strand	10-11	2	13
β-strand	17-25	9	12
α-helix	29-31	3
β-strand	34-39	6	13
β-strand	45-51	7	13
β-strand	58-60	3	13
α-helix	62-64	3
β-strand	68-73	6	12
β-strand	78-84	7	12
α-helix	88-90	3
β-strand	92-98	7	13
β-strand	118	1	13
β-strand	122-125	4	13

Chain P: 1 helix, 0 β-strands

Element	Residues	Length	Sheet
α-helix	2-28	27

Chain R: 15 helices, 7 β-strands

Element	Residues	Length	Sheet
α-helix	32-48	17
β-strand	61	1	1
α-helix	62-63	2
β-strand	65	1	2
β-strand	70	1	2
β-strand	74	1	1
β-strand	78-83	6	3
α-helix	84-85	2
β-strand	98-103	6	3
β-strand	113-114	2	3
α-helix	116-118	3
α-helix	125-161	37
α-helix	163-165	3
α-helix	168-193	26
α-helix	209-245	37
α-helix	257-280	24
α-helix	293-327	35
α-helix	333-350	18
α-helix	353-363	11
α-helix	367-389	23
α-helix	390-394	5
α-helix	397-413	17

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Gastric inhibitory polypeptide receptor,Gastric inhibitory polypeptide receptor,human…	R	protein	573	Homo sapiens	P48546 (AlphaFold model)
Tiezepatide	P	protein	39	synthetic construct
Guanine nucleotide-binding protein G(s) subunit alpha isoforms short	A	protein	394	Bos taurus	P04896 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	B	protein	371	Rattus norvegicus	P54311 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2	G	protein	71	Bos taurus	P63212 (AlphaFold model)
Nanobody-35	N	protein	140	synthetic construct

Sequence of entity 1 (R), FASTA

>7FIY_1 Gastric inhibitory polypeptide receptor,Gastric inhibitory polypeptide receptor,human glucose-dependent insulinotropic polypeptide receptor (chains R)
RAETGSKGQTAGELYQRWERYRRECQETLAAAEPPSGLACNGSFDMYVCWDYAAPNATAR
ASCPWYLPWHHHVAAGFVLRQCGSDGQWGLWRDHTQCENPEKNEAFLDQRLILERLQVMY
TVGYSLSLATLLLALLILSLFRRLHCTRNYIHINLFTSFMLRAAAILSRDRLLPRPGPYL
GDQALALWNQALAACRTAQIVTQYCVGANYTWLLVEGVYLHSLLVLVGGSEEGHFRYYLL
LGWGAPALFVIPWVIVRYLYENTQCWERNEVKAIWWIIRTPILMTILINFLIFIRILGIL
LSKLRTRQMRCRDYRLRLARSTLFLVPLLGVHEVVFAPVTEEQARGALRFAKLGFEIFLS
SFQGFLVSVLYCFINKEVQSEIRRGWHHCRLRRSLGEEQRGSSGGGGSGGGGSSGVFTLE
DFVGDWEQTAAYNLDQVLEQGGVSSLLQNLAVSVTPIQRIVRSGENALKIDIHVIIPYEG
LSADQMAQIEEVFKVVYPVDDHHFKVILPYGTLVIDGVTPNMLNYFGRPYEGIAVFDGKK
ITVTGTLWNGNKIIDERLITPDGSMLFRVTINS

Sequence of entity 2 (P), FASTA

>7FIY_2 Tiezepatide (chains P)
YAEGTFTSDYSIALDKIAQKAFVQWLIAGGPSSGAPPPS

Sequence of entity 3 (A), FASTA

>7FIY_3 Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (chains A)
MGCLGNSKTEDQRNEEKAQREANKKIEKQLQKDKQVYRATHRLLLLGAGESGKNTIVKQM
RILHVNGFNGEGGEEDPQAARSNSDGEKATKVQDIKNNLKEAIETIVAAMSNLVPPVELA
NPENQFRVDYILSVMNVPDFDFPPEFYEHAKALWEDEGVRACYERSNEYQLIDCAQYFLD
KIDVIKQDDYVPSDQDLLRCRVLTSGIFETKFQVDKVNFHMFDVGAQRDERRKWIQCFND
VTAIIFVVASSSYNMVIREDNQTNRLQAALKLFDSIWNNKWLRDTSVILFLNKQDLLAEK
VLAGKSKIEDYFPEFARYTTPEDATPEPGEDPRVTRAKYFIRDEFLRISTASGDGRHYCY
PHFTCSVDTENIRRVFNDCRDIIQRMHLRQYELL

Sequence of entity 4 (B), FASTA

>7FIY_4 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 (chains B)
MGSLLQSELDQLRQEAEQLKNQIRDARKACADATLSQITNNIDPVGRIQMRTRRTLRGHL
AKIYAMHWGTDSRLLVSASQDGKLIIWDSYTTNKVHAIPLRSSWVMTCAYAPSGNYVACG
GLDNICSIYNLKTREGNVRVSRELAGHTGYLSCCRFLDDNQIVTSSGDTTCALWDIETGQ
QTTTFTGHTGDVMSLSLAPDTRLFVSGACDASAKLWDVREGMCRQTFTGHESDINAICFF
PNGNAFATGSDDATCRLFDLRADQELMTYSHDNIICGITSVSFSKSGRLLLAGYDDFNCN
VWDALKADRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLKIWNGSSGGGGSGGGGSSG
VSGWRLFKKIS

Sequence of entity 5 (G), FASTA

>7FIY_5 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (chains G)
MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP
FREKKFFCAIL

Sequence of entity 6 (N), FASTA

>7FIY_6 Nanobody-35 (chains N)
MAQVQLQESGGGLVQPGGSLRLSCAASGFTFSNYKMNWVRQAPGKGLEWVSDISQSGASI
SYTGSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCARCPAPFTRDCFDVTSTTYAYR
GQGTQVTVSSHHHHHHEPEA

Ligands and cofactors

ID	Name	Formula	Copies
CLR	Cholesterol	C27 H46 O	6

Primary citation

Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Zhao, F., Zhou, Q., Cong, Z. et al. Nat Commun (2022) 13:1057-1057. DOI 10.1038/s41467-022-28683-0 · PubMed

Other PDB entries of the same protein (UniProt P48546 (AlphaFold model), which also has an AlphaFold model), best resolution first:

2QKH 1.9 Å, Crystal structure of the extracellular domain of human GIP receptor in complex with the…
6DKJ 1.95 Å, human GIPR ECD and Fab complex
9XN3 2.74 Å, Glucose-dependent insulinotropic polypeptide receptor-Gs complex activated by the small…
8WA3 2.86 Å, Cryo-EM structure of peptide free and Gs-coupled GIPR
7DTY 2.98 Å, Structural basis of ligand selectivity conferred by the human glucose-dependent…
4HJ0 3.0 Å, Crystal structure of the human GIPr ECD in complex with Gipg013 Fab at 3-A resolution
7RBT 3.08 Å, cryo-EM structure of human Gastric inhibitory polypeptide receptor GIPR bound to…
7FIN 3.1 Å, Cryo-EM structure of the GIPR/GLP-1R/GCGR triagonist peptide 20-bound human GIPR-Gs…
8ITM 3.13 Å, Cryo-EM structure of GIPR splice variant 2 (SV2) in complex with Gs protein
7VAB 3.2 Å, Cryo-EM structure of the non-acylated tirzepatide (LY3298176)-bound human GIPR-Gs complex
8ITL 3.23 Å, Cryo-EM structure of GIPR splice variant 1 (SV1) in complex with Gs protein
7RA3 3.24 Å, cryo-EM of human Gastric inhibitory polypeptide receptor GIPR bound to GIP

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