8JIT: PDB entry 8JIT

Cryo-EM structure of the GLP-1R/GCGR dual agonist MEDI0382-bound human GCGR-Gs complex. Determined by electron microscopy at 2.91 Å resolution. Released 6 Sept 2023.

Method: Electron microscopy
Resolution: 2.91 Å
Organisms: Homo sapiens, synthetic construct, Rattus norvegicus
Chains: 6
Atoms: 9,193
Mol. weight: 156.99 kDa
Ligands: D6M
Released: 6 Sept 2023

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

Secondary structure: helices and β-sheets

8JIT contains 40 α-helices and 51 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: 12 helices, 6 β-strands

Element	Residues	Length	Sheet
α-helix	4-33	30
β-strand	35-41	7	1
α-helix	47-49	3
β-strand	194-198	5	1
β-strand	201-207	7	1
α-helix	215-218	4
α-helix	219-221	3
β-strand	227-233	7	1
α-helix	249-261	13
β-strand	270-276	7	1
α-helix	279-282	4
α-helix	284-287	4
α-helix	292-295	4
α-helix	297-301	5
α-helix	309-311	3
α-helix	316-335	20
β-strand	343-347	5	1
α-helix	352-374	23

Chain B: 4 helices, 28 β-strands

Element	Residues	Length	Sheet
α-helix	5-25	21
α-helix	30-33	4
α-helix	38-39	2
β-strand	47-51	5	2
β-strand	58-63	6	3
β-strand	70-74	5	3
β-strand	78-81	4	3
β-strand	91-94	4	3
β-strand	100-105	6	4
β-strand	111-116	6	4
β-strand	121-125	5	4
β-strand	134-139	6	4
β-strand	149-151	3	5
β-strand	156-159	4	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	207-212	6	6
β-strand	217-223	7	6
β-strand	229-234	6	7
β-strand	240-245	6	7
β-strand	250-254	5	7
α-helix	255-257	3
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	307-308	2	8
β-strand	315-320	6	2
β-strand	327-331	5	2
β-strand	336-339	4	2

Chain C: 3 helices, 0 β-strands

Element	Residues	Length
α-helix	9-20	12
α-helix	30-43	14
α-helix	53-55	3

Chain N: 3 helices, 12 β-strands

Element	Residues	Length	Sheet
β-strand	3-7	5	9
β-strand	11-12	2	10
β-strand	18-25	8	9
α-helix	29-31	3
β-strand	34-39	6	11
β-strand	45-51	7	11
β-strand	58-60	3	11
α-helix	62-64	3
β-strand	68-73	6	9
β-strand	78-83	6	9
α-helix	88-90	3
β-strand	92-98	7	11
β-strand	118	1	11
β-strand	122-124	3	11
β-strand	125-126	2	10

Chain P: 1 helix, 0 β-strands

Element	Residues	Length	Sheet
α-helix	2-28	27

Chain R: 17 helices, 5 β-strands

Element	Residues	Length	Sheet
α-helix	29-48	20
β-strand	57	1	12
β-strand	72	1	12
β-strand	75-80	6	13
α-helix	81-82	2
α-helix	88-90	3
β-strand	95-100	6	13
β-strand	106	1	13
α-helix	113-115	3
α-helix	127-164	38
α-helix	172-201	30
α-helix	209-216	8
α-helix	221-254	34
α-helix	258-259	2
α-helix	264-271	8
α-helix	274-288	15
α-helix	301-303	3
α-helix	305-316	12
α-helix	319-333	15
α-helix	344-353	10
α-helix	375-401	27
α-helix	405-419	15

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Guanine nucleotide-binding protein G(s) subunit alpha isoforms short	A	protein	394	Homo sapiens	P63092 (AlphaFold model)
MEDI0382	P	protein	29	synthetic construct
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	B	protein	345	Rattus norvegicus	P54311 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2	C	protein	70	Bos taurus	P63212 (AlphaFold model)
Nanobody 35	N	protein	140	Escherichia coli
Glucagon receptor	R	protein	405	Homo sapiens	P47871 (AlphaFold model)

Sequence of entity 1 (A), FASTA

>8JIT_1 Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (chains A)
MGCLGNSKTEDQRNEEKAQREANKKIEKQLQKDKQVYRATHRLLLLGAGESGKNTIVKQM
RILHVNGFNGEGGEEDPQAARSNSDGEKATKVQDIKNNLKEAIETIVAAMSNLVPPVELA
NPENQFRVDYILSVMNVPDFDFPPEFYEHAKALWEDEGVRACYERSNEYQLIDCAQYFLD
KIDVIKQADYVPSDQDLLRCRVLTSGIFETKFQVDKVNFHMFDVGAQRDERRKWIQCFND
VTAIIFVVASSSYNMVIREDNQTNRLQAALKLFDSIWNNKWLRDTSVILFLNKQDLLAEK
VLAGKSKIEDYFPEFARYTTPEDATPEPGEDPRVTRAKYFIRDEFLRISTASGDGRHYCY
PHFTCAVDTENIRRVFNDCRDIIQRMHLRQYELL

Sequence of entity 2 (P), FASTA

>8JIT_2 MEDI0382 (chains P)
HSQGTFTSDKSEYLDSERARDFVAWLEAG

Sequence of entity 3 (B), FASTA

>8JIT_3 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 (chains B)
MGSLLQSELDQLRQEAEQLKNQIRDARKACADATLSQITNNIDPVGRIQMRTRRTLRGHL
AKIYAMHWGTDSRLLVSASQDGKLIIWDSYTTNKVHAIPLRSSWVMTCAYAPSGNYVACG
GLDNICSIYNLKTREGNVRVSRELAGHTGYLSCCRFLDDNQIVTSSGDTTCALWDIETGQ
QTTTFTGHTGDVMSLSLAPDTRLFVSGACDASAKLWDVREGMCRQTFTGHESDINAICFF
PNGNAFATGSDDATCRLFDLRADQELMTYSHDNIICGITSVSFSKSGRLLLAGYDDFNCN
VWDALKADRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLKIWN

Sequence of entity 4 (C), FASTA

>8JIT_4 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (chains C)
ASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENPF
REKKFFCAIL

Sequence of entity 5 (N), FASTA

>8JIT_5 Nanobody 35 (chains N)
MAQVQLQESGGGLVQPGGSLRLSCAASGFTFSNYKMNWVRQAPGKGLEWVSDISQSGASI
SYTGSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCARCPAPFTRDCFDVTSTTYAYR
GQGTQVTVSSHHHHHHEPEA

Sequence of entity 6 (R), FASTA

>8JIT_6 Glucagon receptor (chains R)
QVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLP
WHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQVMYT
VGYSLSLGALLLALAILGGLSKLHCTRNAIHANLFASFVLKASSVLVIDGLLRTRYSQKI
GDDLSVSTWLSDGAVAGCRVAAVFMQYGIVANYCWLLVEGLYLHNLLGLATLPERSFFSL
YLGIGWGAPMLFVVPWAVVKCLFENVQCWTSNDNMGFWWILRFPVFLAILINFFIFVRIV
QLLVAKLRARQMHHTDYKFRLAKSTLTLIPLLGVHEVVFAFVTDEHAQGTLRSAKLFFDL
FLSSFQGLLVAVLYCFLNKEVQSELRRRWHRWRLGKVLWEERNTS

Ligands and cofactors

ID	Name	Formula	Copies
D6M	N-hexadecanoyl-L-glutamic acid	C21 H39 N O5	1

Primary citation

Structural analysis of the dual agonism at GLP-1R and GCGR. Li, Y., Zhou, Q., Dai, A. et al. Proc Natl Acad Sci U S A (2023) 120:e2303696120-e2303696120. DOI 10.1073/pnas.2303696120 · 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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