title: Complement C1q-target proteins recognition is inhibited by electric moment effectors.
abstract: Classical complement pathway is an important innate immune mechanism, which is usually triggered by binding of C1q to immunoglobulins, pentraxins and other target molecules. Although the activation of the classical pathway is crucial in the host defence, its undesirable and uncontrolled activation can lead to tissue damage. Thus, understanding the molecular basis of complement activation and its inhibition are of great biomedical importance. Recently, we proposed a mechanism for target recognition and classical pathway activation by C1q, which is likely governed by calcium-controlled reorientation of macromolecular electric moment vectors. Here we sought to define the mechanism of C1q inhibition by low molecular weight disulphate compounds that bind to the globular (gC1q) domain, using experimental, computational docking and theoretical modelling approaches. Our experimental results demonstrate that betulin disulphate (B2S) and 9,9-bis(4'-hydroxyphenyl)fluorene disulphate (F2S) inhibit the interaction of C1q and its recombinant globular modules with target molecules IgG1, C-reactive protein (CRP) and long pentraxin 3 (PTX3). In most C1q-inhibitor docked complexes, there is a reduction of electric moment scalar values and similarly altered direction of electric/dipole moment vectors. This could explain the inhibitory effect by impaired electrostatic steering, lacking optimal target recognition and formation of functional complex. In the presence of the inhibitor, the tilt of gC1q domains is likely to be blocked by the altered direction of the electric moment vector. Thus, the transition from the inactive (closed) towards the active (open) conformation of C1q (i.e. the complement activation signal transmission) will be impaired and the cascade initiation disrupted. These results could serve as a starting point for the exploration of a new form of 'electric moment inhibitors/effectors'.
authors.affiliation: Department of Biochemistry, Sofia University, St. Kliment Ohridski, 8 Dragan Tsankov St., Sofia 1164, Bulgaria.
authors.forename: Lubka
authors.initials: L
authors.lastname: Roumenina
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bureeva
authors.forename: Alexander
authors.initials: A
authors.lastname: Kantardjiev
authors.forename: David
authors.initials: D
authors.lastname: Karlinsky
authors.forename: Julian E
authors.initials: JE
authors.lastname: Andia-Pravdivy
authors.forename: Robert
authors.initials: R
authors.lastname: Sim
authors.forename: Alexander
authors.initials: A
authors.lastname: Kaplun
authors.forename: Michael
authors.initials: M
authors.lastname: Popov
authors.forename: Uday
authors.initials: U
authors.lastname: Kishore
authors.forename: Boris
authors.initials: B
authors.lastname: Atanasov
mesh_terms: D002097:C-Reactive Protein / Q000378:metabolism*; D015922:Complement C1q / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000378:metabolism*; D055672:Static Electricity; D013379:Substrate Specificity / Q000187:drug effects; D013431:Sulfates / Q000494:pharmacology*; D013816:Thermodynamics; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D015922:Complement C1q; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D000683:Serum Amyloid P-Component; D013431:Sulfates; D000099153:Pentraxins