7RBT: PDB entry 7RBT

cryo-EM structure of human Gastric inhibitory polypeptide receptor GIPR bound to tirzepatide. Determined by electron microscopy at 3.08 Å resolution. Released 13 Apr 2022.

Method: Electron microscopy
Resolution: 3.08 Å
Organisms: Homo sapiens, Mus musculus, Lama glama
Chains: 7
Atoms: 10,881
Mol. weight: 196.45 kDa
Ligands: 41Y
Released: 13 Apr 2022

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

Secondary structure: helices and β-sheets

7RBT contains 39 α-helices and 85 β-strands across 7 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, 9 β-strands

Element	Residues	Length	Sheet
α-helix	16-37	22
β-strand	41-45	5	1
α-helix	56-58	3
β-strand	209-213	5	1
β-strand	218-223	6	1
α-helix	235-238	4
β-strand	243	1	1
β-strand	247-249	3	2
α-helix	265-277	13
β-strand	286	1	1
β-strand	288-289	2	3
β-strand	290-292	3	2
α-helix	294-302	9
α-helix	314-316	3
α-helix	332-351	20
β-strand	360-361	2	3
α-helix	372-390	19

Chain B: 5 helices, 30 β-strands

Element	Residues	Length	Sheet
α-helix	4-24	21
α-helix	30-35	6
β-strand	49-51	3	4
β-strand	58-63	6	5
β-strand	69-74	6	5
β-strand	78-83	6	5
β-strand	89-94	6	5
α-helix	95	1
β-strand	100-105	6	6
β-strand	111-116	6	6
β-strand	121-125	5	6
β-strand	134-139	6	6
α-helix	145	1
β-strand	146-149	4	7
β-strand	153	1	8
β-strand	156	1	8
β-strand	158-161	4	7
β-strand	166-170	5	7
β-strand	175-180	6	7
β-strand	187-192	6	9
β-strand	199-203	5	9
β-strand	207-210	4	9
β-strand	220-223	4	9
β-strand	229-234	6	10
β-strand	240-245	6	10
β-strand	250-254	5	10
β-strand	260-264	5	10
α-helix	272-273	2
β-strand	276-277	2	11
β-strand	284-288	5	11
β-strand	294-298	5	11
β-strand	306-308	3	11
β-strand	315-320	6	4
β-strand	327-331	5	4
β-strand	336-339	4	4

Chain E: 4 helices, 24 β-strands

Element	Residues	Length	Sheet
β-strand	4-7	4	12
β-strand	11-12	2	13
β-strand	17-24	8	12
β-strand	33-39	7	14
β-strand	45-51	7	14
α-helix	53-55	3
β-strand	58-60	3	14
β-strand	68-73	6	12
β-strand	78-84	7	12
α-helix	88-90	3
β-strand	93-99	7	14
β-strand	111	1	14
β-strand	115-116	2	14
β-strand	118-119	2	13
β-strand	128	1	15
β-strand	134-136	3	16
β-strand	147	1	17
β-strand	162-167	6	18
β-strand	174-178	5	18
β-strand	182-183	2	18
α-helix	184	1
β-strand	193-196	4	17
β-strand	199-202	4	17
β-strand	214-219	6	18
α-helix	226	1
β-strand	227	1	18
β-strand	228	1	15
β-strand	232-234	3	16

Chain G: 2 helices, 0 β-strands

Element	Residues	Length	Sheet
α-helix	8-23	16
α-helix	30-42	13

Chain N: 3 helices, 15 β-strands

Element	Residues	Length	Sheet
β-strand	3-7	5	19
β-strand	11-12	2	20
β-strand	17-25	9	19
α-helix	29-31	3
β-strand	35-39	5	21
β-strand	41	1	22
β-strand	43	1	22
β-strand	45-50	6	21
β-strand	59-60	2	21
α-helix	62-64	3
β-strand	69-73	5	19
β-strand	78-84	7	19
α-helix	88-90	3
β-strand	92-95	4	21
β-strand	97	1	23
β-strand	118	1	23
β-strand	122-124	3	21
β-strand	125-126	2	20

Chain P: 1 helix, 0 β-strands

Element	Residues	Length	Sheet
α-helix	2-28	27

Chain R: 16 helices, 7 β-strands

Element	Residues	Length	Sheet
α-helix	32-52	21
α-helix	54-56	3
β-strand	64-65	2	24
β-strand	70-71	2	24
β-strand	78-80	3	25
β-strand	83	1	26
α-helix	84-85	2
α-helix	95-96	2
β-strand	98	1	26
β-strand	101-103	3	25
β-strand	109	1	25
α-helix	127-161	35
α-helix	168-192	25
α-helix	210-246	37
α-helix	253-280	28
α-helix	294-326	33
α-helix	337-346	10
α-helix	348-350	3
α-helix	363-365	3
α-helix	369-372	4
α-helix	374-389	16
α-helix	390-394	5
α-helix	397-409	13

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short	A	protein	373	Homo sapiens	P63092 (AlphaFold model), P63096 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	B	protein	350	Homo sapiens	P62873 (AlphaFold model)
Single-chain variable fragment 16	E	protein	297	Mus musculus
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	160	Lama glama
Tirzepatide	P	protein	39	Homo sapiens
Gastric inhibitory polypeptide receptor	R	protein	463	Homo sapiens	P48546

Sequence of entity 1 (A), FASTA

>7RBT_1 Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (chains A)
MGCTLSAEDKAAVERSKMIEKQLQKDKQVYRATHRLLLLGAGESGKSTIVKQMRILHVNG
FNGDSEKATKVQDIKNNLKEAIETIVAAMSNLVPPVELANPENQFRVDYILSVMNVPDFD
FPPEFYEHAKALWEDEGVRACYERSNEYQLIDCAQYFLDKIDVIKQADYVPSDQDLLRCR
VLTSGIFETKFQVDKVNFHMFDVGGQRDERRKWIQCFNDVTAIIFVVASSSYNMVIREDN
QTNRLQEALNLFKSIWNNRWLRTISVILFLNKQDLLAEKVLAGKSKIEDYFPEFARYTTP
EDATPEPGEDPRVTRAKYFIRDEFLRISTASGDGRHYCYPHFTCAVDTENIRRVFNDCRD
IIQRMHLRQYELL

Sequence of entity 2 (B), FASTA

>7RBT_2 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 (chains B)
MHHHHHHGSSGSELDQLRQEAEQLKNQIRDARKACADATLSQITNNIDPVGRIQMRTRRT
LRGHLAKIYAMHWGTDSRLLVSASQDGKLIIWDSYTTNKVHAIPLRSSWVMTCAYAPSGN
YVACGGLDNICSIYNLKTREGNVRVSRELAGHTGYLSCCRFLDDNQIVTSSGDTTCALWD
IETGQQTTTFTGHTGDVMSLSLAPDTRLFVSGACDASAKLWDVREGMCRQTFTGHESDIN
AICFFPNGNAFATGSDDATCRLFDLRADQELMTYSHDNIICGITSVSFSKSGRLLLAGYD
DFNCNVWDALKADRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLKIWN

Sequence of entity 3 (E), FASTA

>7RBT_3 Single-chain variable fragment 16 (chains E)
MLLVNQSHQGFNKEHTSKMVSAIVLYVLLAAAAHSAFADVQLVESGGGLVQPGGSRKLSC
SASGFAFSSFGMHWVRQAPEKGLEWVAYISSGSGTIYYADTVKGRFTISRDDPKNTLFLQ
MTSLRSEDTAMYYCVRSIYYYGSSPFDFWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQ
ATSSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRMSNLASGVPDR
FSGSGSGTAFTLTISRLEAEDVGVYYCMQHLEYPLTFGAGTKLELKAAAHHHHHHHH

Sequence of entity 4 (G), FASTA

>7RBT_4 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (chains G)
MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP
FREKKFFCAIL

Sequence of entity 5 (N), FASTA

>7RBT_5 nanobody 35 (chains N)
MKYLLPTAAAGLLLLAAQPAMAQVQLQESGGGLVQPGGSLRLSCAASGFTFSNYKMNWVR
QAPGKGLEWVSDISQSGASISYTGSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCAR
CPAPFTRDCFDVTSTTYAYRGQGTQVTVSSHHHHHHEPEA

Sequence of entity 6 (P), FASTA

>7RBT_6 Tirzepatide (chains P)
YAEGTFTSDYSIALDKIAQKAFVQWLIAGGPSSGAPPPS

Sequence of entity 7 (R), FASTA

>7RBT_7 Gastric inhibitory polypeptide receptor (chains R)
DYKDDDDAAALEVLFQGPRAETGSKGQTAGELYQRWERYRRECQETLAAAEPPSGLACNG
SFDMYVCWDYAAPNATARASCPWYLPWHHHVAAGFVLRQCGSDGQWGLWRDHTQCENPEK
NEAFLDQRLILERLQVMYTVGYSLSLATLLLALLILSLFRRLHCTRNYIHINLFTSFMLR
AAAILSRDRLLPRPGPYLGDQALALWNQALAACRTAQIVTQYCVGANYTWLLVEGVYLHS
LLVLVGGSEEGHFRYYLLLGWGAPALFVIPWVIVRYLYENTQCWERNEVKAIWWIIRTPI
LMTILINFLIFIRILGILLSKLRTRQMRCRDYRLRLARSTLTLVPLLGVHEVVFAPVTEE
QARGALRFAKLGFEIFLSSFQGFLVSVLYCFINKEVQSEIRRGWHHCRLRRSLGEEQRQL
PERAFRALPSGSGPGEVPTSRGLSSGTLPGPGNEASRELESYC

Ligands and cofactors

ID	Name	Formula	Copies
41Y	2-fluoro-4-[(1R)-6-methoxy-1-methyl-2-{(1S)-1-[4-(propan-2-yl)phenyl]ethyl}-1,2…	C32 H41 F N2 O2	1

Primary citation

Structural determinants of dual incretin receptor agonism by tirzepatide. Sun, B., Willard, F.S., Feng, D. et al. Proc Natl Acad Sci U S A (2022) 119:e2116506119-e2116506119. DOI 10.1073/pnas.2116506119 · 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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