Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Apr 13:21:2579-2590.
doi: 10.1016/j.csbj.2023.04.008. eCollection 2023.

The CDR3 region as the major driver of TREM-1 interaction with its ligands, an in silico characterization

Amanda de Oliveira Matos  1 , Pedro Henrique Dos Santos Dantas  1 , Mike Telemaco Contreras Colmenares  1 , Geraldo Rodrigues Sartori  2 , Marcelle Silva-Sales  1 , João Herminio Martins Da Silva  2 , Bruno Junior Neves  3 , Carolina Horta Andrade  3 , Helioswilton Sales-Campos  1
Affiliations

The CDR3 region as the major driver of TREM-1 interaction with its ligands, an in silico characterization

Amanda de Oliveira Matos et al. Comput Struct Biotechnol J. .

Abstract

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor heavily investigated in infectious and non-infectious diseases. Because of its role in amplifying inflammation, TREM-1 has been explored as a diagnostic/prognostic biomarker. Further, as the receptor has been implicated in the pathophysiology of several diseases, therapies aiming at modulating its activity represent a promising strategy to constrain uncontrolled inflammatory or infectious diseases. Despite this, several aspects concerning its interaction with ligands and activation process, remain unclear. Although many molecules have been suggested as TREM-1 ligands, only five have been confirmed to interact with the receptor: actin, eCIRP, HMGB1, Hsp70 and PGLYRP1. However, the domains involved in the interaction between the receptor and these proteins are not clarified yet. Therefore, here we used in silico approaches to investigate the putative binding domains in the receptor, using hot spots analysis, molecular docking and molecular dynamics simulations between TREM-1 and its five known ligands. Our results indicated the complementarity-determining regions (CDRs) of the receptor as the main mediators of antigen recognition, especially the CDR3 loop. We believe that our study could be used as structural basis for the elucidation of TREM-1's recognition process, and may be useful for prospective in silico and biological investigations exploring the receptor in different contexts.

Keywords: Binding domain; CDR3; Pattern recognition receptor; TREM-1; TREM-1 ligands.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Helioswilton Sales-Campos reports financial support was provided by Fundação de Apoio a Pesquisa (FUNAPE). Carolina Horta Andrade reports a relationship with Fundação de Amparo a Pesquisa do Estado de Goiás (FAPEG) that includes: funding grants. Bruno Junior Neves reports a relationship with Fundação de Amparo a Pesquisa do Estado de Goiás (FAPEG) that includes: funding grants. Carolina Horta Andrade reports a relationship with Conselho Nacional de Desenvolvimento Científico (CNPq) that includes: funding grants. Bruno Junior Neves reports a relationship with Conselho Nacional de Desenvolvimento Científico (CNPq) that includes: funding grants. Helioswilton Sales-Campos reports a relationship with Fundação de Amparo a Pesquisa (FUNAPE) that includes: funding grants. Bruno Junior Neves reports a relationship with Fundação de Amparo a Pesquisa (FUNAPE) that includes: funding grants.

Figures

ga1
Graphical abstract
Fig. 1
Fig. 1
Hot spots analysis in the IgV-like domain of the triggering receptor expressed on myeloid cells (TREM-1). (A) The Complementarity-determining regions (CDRs) of TREM-1. CDR1 in yellow, CDR2 in orange and CDR3 in red. (B) The interaction of FTMap probe clusters with TREM-1, highlighting the interaction with CDR1 (yellow), CDR2 (orange) and CDR3 (red). TREM-1 amino acids mediating nonbonded, in cyan (C), and H-bonded, in blue (D) interactions, from the FTMap analysis. (E) Amino acids predicted as possibly “interactive” by SeRenDIP, in pink. (F) Amino acids predicted as hot spots by both FTMap and SeRenDIP, in gray.
Fig. 2
Fig. 2
Predicted TREM-1/ligands complexes. (A) TREM-1 and actin, (B) TREM-1 and APOA1, the negative control, (C) TREM-1 and eCIRP, (D) TREM-1 and HMGB1, (E) TREM-1 and Hsp70, (F) TREM-1 and PGLYRP1. Ramachandran plots for the complexes: TREM-1/actin (G), TREM-1/APOA1 (H), TREM-1/eCIRP (I), TREM-1/HMGB1 (J), TREM-1/Hsp70 (K), TREM-1/PGLYRP1 (L).
Fig. 3
Fig. 3
The simulated TREM-1/actin and TREM-1/PGLYRP1 complexes. (A – D) TREM-1 (green) and actin (gray), with interacting residues in yellow and cyan, respectively. (C) Hydrogen bonds in TREM-1/actin predicted by DIMPLOT. (D) Combination of residues with binding free energies < −1 kcal/mol and/or involved in hydrogen bonds or salt bridges from TREM-1/actin. Yellow: TREM-1 residues, cyan: actin residues. (E – H) TREM-1 (green) and PGLYRP1 (gray), with interacting residues in yellow and cyan, respectively. (G) Hydrogen bonds and salt bridges in TREM-1/PGLYRP1 predicted by DIMPLOT. (H) Combination of residues with binding free energies < −1 kcal/mol and/or involved in hydrogen bonds or salt bridges from TREM-1/PGLYRP1. Yellow: TREM-1 residues, cyan: PGLYRP1 residues.
Fig. 4
Fig. 4
Molecular dynamics simulations for TREM-1/actin and TREM-1/PGLYRP1. (A) Last frames of each replicate of the TREM1 complex with (A) actin and (B) PGLYRP1, represented in ribbons. The interface RMSD during the five replicate stepwise heated simulations for the (C) TREM-1/actin and (D) TREM-1/PGLYRP1 complexes are also shown. The interface RMSD for each simulation during the extended conventional MD is illustrated in (E) and (F) for TREM1-Actin and TREM1-PGLYRP1, respectively. Each color of the lines represents one replicate and corresponds to the color of the ribbons. The green ribbons represent the reference structure obtained from AlphaFold2-Multimer. Sticks are used to depict the residues performing the most relevant interactions. Dashed lines represents a cutoff of acceptable interface RMSD during the simulations.
Fig. 5
Fig. 5
The putative binding domains on TREM-1. (A) Residues from the IgV-like domain of TREM-1 observed in the interaction interfaces (*residues with binding free energies <−1 kcal/mol and/or involved in hydrogen bonds or salt bridges) and in the hot spots analysis. (B) Full structure of TREM-1 with its different domains and the predicted putative binding domain (in yellow). PDB file downloaded from the Alphafold database (https://alphafold.ebi.ac.uk/entry/Q9NP99).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Bosco M.C., Pierobon D., Blengio F., Raggi F., Vanni C., Gattorno M., et al. Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo. Blood. 2011;117:2625–2639. - PubMed
    1. Bouchon A., Dietrich J., Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 1950;164(2000):4991–4995. - PubMed
    1. Gingras M.C., Lapillonne H., Margolin J.F. TREM-1, MDL-1, and DAP12 expression is associated with a mature stage of myeloid development. Mol Immunol. 2002;38:817–824. - PubMed
    1. de Oliveira Matos A., Dos Santos Dantas P.H., Figueira Marques Silva-Sales M., Sales-Campos H. The role of the triggering receptor expressed on myeloid cells-1 (TREM-1) in non-bacterial infections. Crit Rev Microbiol. 2020;46:237–252. - PubMed
    1. Matos A.O., Dantas P., Silva-Sales M., Sales-Campos H. TREM-1 isoforms in bacterial infections: to immune modulation and beyond. Crit Rev Microbiol. 2021;47:290–306. - PubMed

LinkOut - more resources