Stereoelectronic Effects Impact Glycan Recognition.

Area of Science:

• Structural Biology
• Carbohydrate Chemistry
• Immunology

Background:

• Lectins are proteins that recognize and bind specific glycans, playing crucial roles in biological processes.
• Human intelectin-1 (hItln-1), a soluble lectin, exhibits unusual broad specificity for microbial sugars, including those with an exocyclic vicinal diol.
• The precise structural basis and specificity determinants for hItln-1 glycan recognition remained unclear.

Purpose of the Study:

• To elucidate the structural mechanisms underlying human intelectin-1 (hItln-1) recognition of microbial glycans.
• To investigate the role of specific glycan conformations and stereoelectronic effects in hItln-1 binding.
• To understand how hItln-1 achieves specificity despite binding glycans with a common structural feature.

Main Methods:

• X-ray crystallography was employed to determine the high-resolution structure of the hItln-1·KO complex.
• Bioinformatic analysis of glycan conformations in the Protein Data Bank was performed.
• Natural bond orbital (NBO) calculations were utilized to assess stabilizing forces in glycan conformations.

Main Results:

• The crystal structure revealed the bound conformation of d-glycero-d-talo-oct-2-ulosonic acid (KO) with hItln-1.
• KO and 3-deoxy-d-manno-oct-2-ulosonic acid (KDO) adopt a common conformation that favors hItln-1 binding, unlike heptoses.
• Stereoelectronic effects, in addition to steric factors, stabilize these preferred conformations, influencing hItln-1 specificity.

Conclusions:

• Human intelectin-1 (hItln-1) specificity is dictated by stereoelectronic effects that stabilize preferred glycan conformations.
• hItln-1 avoids binding prevalent glycans with terminal 1,2-diols, such as N-acetyl-neuraminic acid and l-glycero-α-d-manno-heptose.
• This selective binding suggests hItln-1 has evolved to specifically target distinct bacterial species.