PDBsum entry 5d3i

Immune system

PDB id: 5d3i

Contents

Protein chains

549 a.a.

190 a.a.

Ligands

NAG-NAG

NAG

PCW

Metals

_CL

PDB id:

5d3i

Name:

Immune system

Title:

Crystal structure of the ssl3-tlr2 complex

Structure:

Toll-like receptor 2. Chain: a. Fragment: unp residues 25-589. Engineered: yes. Staphylococcal superantigen-like protein 3. Chain: b. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: tlr2. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293-ebna1-s. Staphylococcus aureus (strain nctc 8325). Organism_taxid: 93061.

Resolution:

3.20Å R-factor: 0.233 R-free: 0.271

Authors:

L.J.Feitsma,E.G.Huizinga

Key ref:

K.J.Koymans et al. (2015). Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3). Proc Natl Acad Sci U S A, 112, 11018-11023. PubMed id: 26283364 DOI: 10.1073/pnas.1502026112

Date:

06-Aug-15 Release date: 19-Aug-15

Protein chain

Q9QUN7  (TLR2_MOUSE) -  Toll-like receptor 2 from Mus musculus

Seq: 784 a.a.

Struc: 549 a.a.

Protein chain

Q2G0X7  (Q2G0X7_STAA8) -  Staphylococcal superantigen-like 3 from Staphylococcus aureus (strain NCTC 8325 / PS 47)

Seq: 356 a.a.

Struc: 190 a.a.

Enzyme reactions

• Enzyme class: Chain A: 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 + H(+) (Bound ligand (Het Group name = NAG) matches with 43.75% similarity)

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

reference

DOI no: 10.1073/pnas.1502026112

Proc Natl Acad Sci U S A 112:11018-11023 (2015)

PubMed id: 26283364

Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3).

K.J.Koymans, L.J.Feitsma, T.H.Brondijk, P.C.Aerts, E.Lukkien, P.Lössl, K.P.van Kessel, C.J.de Haas, J.A.van Strijp, E.G.Huizinga.

ABSTRACT

Toll-like receptors (TLRs) are crucial in innate recognition of invading micro-organisms and their subsequent clearance. Bacteria are not passive bystanders and have evolved complex evasion mechanisms. Staphylococcus aureus secretes a potent TLR2 antagonist, staphylococcal superantigen-like protein 3 (SSL3), which prevents receptor stimulation by pathogen-associated lipopeptides. Here, we present crystal structures of SSL3 and its complex with TLR2. The structure reveals that formation of the specific inhibitory complex is predominantly mediated by hydrophobic contacts between SSL3 and TLR2 and does not involve interaction of TLR2-glycans with the conserved Lewis(X) binding site of SSL3. In the complex, SSL3 partially covers the entrance to the lipopeptide binding pocket in TLR2, reducing its size by ∼50%. We show that this is sufficient to inhibit binding of agonist Pam2CSK4 effectively, yet allows SSL3 to bind to an already formed TLR2-Pam2CSK4 complex. The binding site of SSL3 overlaps those of TLR2 dimerization partners TLR1 and TLR6 extensively. Combined, our data reveal a robust dual mechanism in which SSL3 interferes with TLR2 activation at two stages: by binding to TLR2, it blocks ligand binding and thus inhibits activation. Second, by interacting with an already formed TLR2-lipopeptide complex, it prevents TLR heterodimerization and downstream signaling.