In meso crystal structure and docking simulations suggest an alternative proteoglycan binding site in the OpcA outer membrane adhesin

Vadim Cherezov, Wei Liu, Jeremy P. Derrick, Binquan Luan, Aleksei Aksimentiev, Vsevolod Katritch, Martin Caffrey

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

OpcA is an integral outer membrane adhesin protein from Neisseria meningitidis, the causative agent of meningococcal meningitis and septicemia. It binds to sialic acid (SA)-containing polysaccharides on the surface of epithelial cells. The crystal structure of OpcA showed that the protein adopts a 10-stranded β-barrel structure, with five extensive loop regions on the extracellular side of the membrane. These form a crevice structure, lined with basic residues, which was hypothesized to act as the binding site for polysaccharide ligands. In the current study, a distinctly different OpcA structure has been obtained using crystals grown from a lipidic mesophase. Comparison of the two structures shows that the largest loop (L2), which closes over the end of the β-barrel in the original crystal form, adopts a much more extended structure by reaching outward and away from the protein. The difference in conformation may be attributable to the absence of zinc ions from the crystallization conditions for the in meso crystal form: in the original structure, two zinc ions were bound to the external loops. Molecular dynamics (MD) simulations performed on the two OpcA modeh in a lipid bilayer environment demonstrated pronounced loop mobility. These observations support the view that the loop regions of OpcA are capable of a high degree of conformational flexibility. The original binding site for polysaccharide is not present in the in meso crystal form, and is disrupted during MD simulations. Docking analysis suggests a putative alternative location for the SA ligand in the new crystal form of OpcA.

Original languageEnglish (US)
Pages (from-to)24-34
Number of pages11
JournalProteins: Structure, Function and Genetics
Volume71
Issue number1
DOIs
StatePublished - Apr 2008
Externally publishedYes

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Proteoglycans
Polysaccharides
Crystal structure
Binding Sites
N-Acetylneuraminic Acid
Molecular Dynamics Simulation
Membranes
Crystals
Zinc
Meningococcal Meningitis
Ions
Ligands
Neisseria meningitidis
Lipid Bilayers
Molecular dynamics
Crystallization
Sepsis
Membrane Proteins
Proteins
Epithelial Cells

Keywords

  • Lipidic cubic phase
  • Membrane protein crystallization
  • Molecular dynamics
  • Sialic acid
  • X-ray diffraction

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

Cite this

In meso crystal structure and docking simulations suggest an alternative proteoglycan binding site in the OpcA outer membrane adhesin. / Cherezov, Vadim; Liu, Wei; Derrick, Jeremy P.; Luan, Binquan; Aksimentiev, Aleksei; Katritch, Vsevolod; Caffrey, Martin.

In: Proteins: Structure, Function and Genetics, Vol. 71, No. 1, 04.2008, p. 24-34.

Research output: Contribution to journalArticle

Cherezov, Vadim ; Liu, Wei ; Derrick, Jeremy P. ; Luan, Binquan ; Aksimentiev, Aleksei ; Katritch, Vsevolod ; Caffrey, Martin. / In meso crystal structure and docking simulations suggest an alternative proteoglycan binding site in the OpcA outer membrane adhesin. In: Proteins: Structure, Function and Genetics. 2008 ; Vol. 71, No. 1. pp. 24-34.
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