PDBsum entry 5ijd

Immune system

PDB id: 5ijd

Contents

Protein chains

590 a.a.

137 a.a.

Ligands

NAG-NAG ×7

NAG ×5

LP4-LP5-DAO-MYR ×2

Waters ×232

PDB id:

5ijd

Name:

Immune system

Title:

The crystal structure of mouse tlr4/md-2/lipid a complex

Structure:

Toll-like receptor 4, variable lymphocyte receptor b chimera. Chain: a, b. Fragment: tlr4 ectodomain (unp residues 26-544) + vlrb (unp residues 126-200). Engineered: yes. Lymphocyte antigen 96. Chain: c, d. Fragment: unp residues 19-160.

Source:

Mus musculus, eptatretus burgeri. Mouse, inshore hagfish. Organism_taxid: 10090, 7764. Gene: tlr4, lps, vlrb. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Mus musculus. Mouse. Organism_taxid: 10090.

Resolution:

2.70Å R-factor: 0.217 R-free: 0.285

Authors:

Y.Wang,L.Su,M.D.Morin,B.T.Jones,L.R.Whitby,M.Surakattula,H.Huang, H.Shi,J.H.Choi,K.Wang,E.M.Moresco,M.Berger,X.Zhan,H.Zhang,D.L.Boger, B.Beutler

Key ref:

Y.Wang et al. (2016). TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS. Proc Natl Acad Sci U S A, 113, E884. PubMed id: 26831104 DOI: 10.1073/pnas.1525639113

Date:

01-Mar-16 Release date: 27-Apr-16

Supersedes:

5hg6

Protein chains

Q4G1L2  (Q4G1L2_EPTBU) -  Variable lymphocyte receptor B from Eptatretus burgeri

Seq: 273 a.a.

Struc: 590 a.a.*

Protein chains

Q9QUK6  (TLR4_MOUSE) -  Toll-like receptor 4 from Mus musculus

Seq: 835 a.a.

Struc: 590 a.a.*

Protein chains

Q9JHF9  (LY96_MOUSE) -  Lymphocyte antigen 96 from Mus musculus

Seq: 160 a.a.

Struc: 137 a.a.

* PDB and UniProt seqs differ at 160 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.2.2.6 - ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase.
• Reaction: NAD⁺ + H2O = ADP-D-ribose + nicotinamide + H⁺

NAD(+) + H2O = ADP-D-ribose + nicotinamide (Bound ligand (Het Group name = NAG) matches with 43.75% similarity) + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1073/pnas.1525639113

Proc Natl Acad Sci U S A 113:E884 (2016)

PubMed id: 26831104

TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS.

Y.Wang, L.Su, M.D.Morin, B.T.Jones, L.R.Whitby, M.M.Surakattula, H.Huang, H.Shi, J.H.Choi, K.W.Wang, E.M.Moresco, M.Berger, X.Zhan, H.Zhang, D.L.Boger, B.Beutler.

ABSTRACT

Structurally disparate molecules reportedly engage and activate Toll-like receptor (TLR) 4 and other TLRs, yet the interactions that mediate binding and activation by dissimilar ligands remain unknown. We describe Neoseptins, chemically synthesized peptidomimetics that bear no structural similarity to the established TLR4 ligand, lipopolysaccharide (LPS), but productively engage the mouse TLR4 (mTLR4)/myeloid differentiation factor 2 (MD-2) complex. Neoseptin-3 activates mTLR4/MD-2 independently of CD14 and triggers canonical myeloid differentiation primary response gene 88 (MyD88)- and Toll-interleukin 1 receptor (TIR) domain-containing adaptor inducing IFN-beta (TRIF)-dependent signaling. The crystal structure mTLR4/MD-2/Neoseptin-3 at 2.57-Å resolution reveals that Neoseptin-3 binds as an asymmetrical dimer within the hydrophobic pocket of MD-2, inducing an active receptor complex similar to that induced by lipid A. However, Neoseptin-3 and lipid A form dissimilar molecular contacts to achieve receptor activation; hence strong TLR4/MD-2 agonists need not mimic LPS.