8WO1: Human TLR4/MD-2/DLAM5 Complex

Cryo-EM Structure of Human TLR4/MD-2/DLAM5 Complex. Determined by electron microscopy at 2.24 Å resolution. Released 9 Oct 2024.

Method: Electron microscopy
Resolution: 2.24 Å
Organism: Homo sapiens
Chains: 4
Atoms: 12,406
Mol. weight: 178.6 kDa
Ligands: NAG, GP4, 2IL, 0IL
Released: 9 Oct 2024

Explore 8WO1 in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

8WO1 contains 22 α-helices and 126 β-strands across 4 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.

Chains A and B: 8 helices, 53 β-strands

Element	Residues	Length	Sheet
β-strand	30-33	4	1
β-strand	37-39	3	1
β-strand	55	1	2
β-strand	57-60	4	1
β-strand	68-69	2	3
β-strand	79	1	2
β-strand	82	1	4
β-strand	83-84	2	1
β-strand	92-93	2	3
α-helix	94	1
β-strand	102	1	2
β-strand	106-108	3	4
β-strand	116-117	2	3
β-strand	130-132	3	4
β-strand	154-156	3	4
α-helix	169-171	3
β-strand	179-181	3	4
β-strand	189-190	2	5
β-strand	207-209	3	4
β-strand	217-218	2	5
β-strand	223	1	6
β-strand	228	1	7
β-strand	230-234	5	4
α-helix	240-249	10
β-strand	250	1	6
β-strand	255	1	7
β-strand	257-261	5	4
β-strand	287-291	5	4
β-strand	312-316	5	4
β-strand	319	1	8
β-strand	334-338	5	4
β-strand	341	1	8
β-strand	349	1	9
β-strand	355-359	5	4
β-strand	371	1	9
β-strand	377-379	3	4
α-helix	393-396	4
β-strand	403-405	3	4
β-strand	412-413	2	10
β-strand	426-428	3	4
β-strand	434-435	2	10
β-strand	451-453	3	4
β-strand	460-461	2	11
β-strand	475-477	3	4
β-strand	482-483	2	11
α-helix	484-486	3
β-strand	487-488	2	12
β-strand	500-502	3	4
β-strand	510-511	2	12
β-strand	524-526	3	4
β-strand	534	1	13
β-strand	548-550	3	4
β-strand	558	1	13
α-helix	566-568	3
β-strand	573-575	3	4
β-strand	581	1	14
α-helix	588-595	8
α-helix	604-606	3
β-strand	608	1	15
β-strand	609	1	14
β-strand	619	1	15

Chains C and D: 3 helices, 10 β-strands

Element	Residues	Length	Sheet
β-strand	22-23	2	31
β-strand	33-36	4	31
β-strand	45-49	5	32
α-helix	51-53	3
β-strand	57-65	9	32
β-strand	75-82	8	31
β-strand	85-86	2	31
α-helix	87-89	3
β-strand	90-93	4	31
α-helix	104-106	3
β-strand	113-121	9	32
β-strand	129-139	11	31
β-strand	144-155	12	31

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Toll-like receptor 4	A, B	protein	605	Homo sapiens	O00206 (AlphaFold model)
Lymphocyte antigen 96	C, D	protein	142	Homo sapiens	Q9Y6Y9 (AlphaFold model)

Sequence of entity 1 (A, B), FASTA

>8WO1_1 Toll-like receptor 4 (chains A, B)
EPCVEVVPNITYQCMELNFYKIPDNLPFSTKNLDLSFNPLRHLGSYSFFSFPELQVLDLS
RCEIQTIEDGAYQSLSHLSTLILTGNPIQSLALGAFSGLSSLQKLVAVETNLASLENFPI
GHLKTLKELNVAHNLIQSFKLPEYFSNLTNLEHLDLSSNKIQSIYCTDLRVLHQMPLLNL
SLDLSLNPMNFIQPGAFKEIRLHKLTLRNNFDSLNVMKTCIQGLAGLEVHRLVLGEFRNE
GNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDIIDLFNCLTNVSSFSLVSVTIERVKDF
SYNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTSNKGGNAFSEVDLPSLEFLDLSRNGLS
FKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFLGLEQLEHLDFQHSNLKQMSEFSVFLSL
RNLIYLDISHTHTRVAFNGIFNGLSSLEVLKMAGNSFQENFLPDIFTELRNLTFLDLSQC
QLEQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPYKCLNSLQVLDYSLNHIMTSKKQELQH
FPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQLLVEVERMECATPSDKQGMPVLSLNIT
CQMNK

Sequence of entity 2 (C, D), FASTA

>8WO1_2 Lymphocyte antigen 96 (chains C, D)
QKQYWVCNSSDASISYTYCDKMQYPISINVNPCIELKGSKGLLHIFYIPRRDLKQLYFNL
YITVNTMNLPKRKEVICRGSDDDYSFCRALKGETVNTTISFSFKGIKFSKGKYKCVVEAI
SGSPEEMLFCLEFVILHQPNSN

Ligands and cofactors

ID	Name	Formula	Copies
NAG	2-acetamido-2-deoxy-beta-D-glucopyranose	C8 H15 N O6	6
GP4	2-amino-2-deoxy-4-O-phosphono-alpha-D-glucopyranose	C6 H14 N O8 P	2
2IL	(3R)-3-(dodecanoyloxy)tetradecanoic acid	C26 H50 O4	2
0IL	(3R)-3-(tetradecanoyloxy)tetradecanoic acid	C28 H54 O4	2
X6N	[(2~{R},3~{S},4~{R},5~{S})-2-(hydroxymethyl)-5-methoxy-4,6-bis(oxidanyl)oxan-3-…	C7 H15 O9 P	2
A1L01	(3~{S})-3-decanoyloxytetradecanoic acid	C24 H46 O4	2

Primary citation

Structural insight into TLR4/MD-2 activation by synthetic LPS mimetics with distinct binding modes. Fu, Y., Kim, H., Lee, D.S. et al. Nat Commun (2025) 16:4164-4164. DOI 10.1038/s41467-025-59550-3 · PubMed

Other PDB entries of the same protein (UniProt O00206 (AlphaFold model), which also has an AlphaFold model), best resolution first:

2Z62 1.7 Å, Crystal structure of the TV3 hybrid of human TLR4 and hagfish VLRB.61
2Z66 1.9 Å, Crystal structure of the VT3 hybrid of human TLR4 and hagfish VLRB.61
2Z63 2.0 Å, Crystal structure of the TV8 hybrid of human TLR4 and hagfish VLRB.61
3UL7 2.37 Å, Crystal structure of the TV3 mutant F63W
4G8A 2.4 Å, Crystal structure of human TLR4 polymorphic variant D299G and T399I in complex with MD-2…
3UL9 2.45 Å, structure of the TV3 mutant M41E
3UL8 2.5 Å, Crystal structure of the TV3 mutant V134L
2Z65 2.7 Å, Crystal structure of the human TLR4 TV3 hybrid-MD-2-Eritoran complex
9J03 2.7 Å, Cyro-EM Structure of Human TLR4/MD-2/DLAM1 Complex
8WTA 2.9 Å, Cryo-EM Structure of Human TLR4/MD-2/DLAM3 Complex
3FXI 3.1 Å, Crystal structure of the human TLR4-human MD-2-E.coli LPS Ra complex
3ULA 3.6 Å, Crystal structure of the TV3 mutant F63W-MD-2-Eritoran complex

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