Complement C1q-target proteins recognition is inhibited by electric moment effectors.
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'.
Roumenina
Lubka
L
Department of Biochemistry, Sofia University, St. Kliment Ohridski, 8 Dragan Tsankov St., Sofia 1164, Bulgaria.
Bureeva
Svetlana
S
Kantardjiev
Alexander
A
Karlinsky
David
D
Andia-Pravdivy
Julian E
JE
Sim
Robert
R
Kaplun
Alexander
A
Popov
Michael
M
Kishore
Uday
U
Atanasov
Boris
B
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
D002097:C-Reactive Protein; D015922:Complement C1q; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D000683:Serum Amyloid P-Component; D013431:Sulfates; D000099153:Pentraxins