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Related Concept Videos

Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
Complement System01:27

Complement System

The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a membrane...
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.

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Related Experiment Video

Updated: Jun 2, 2026

High-resolution Melting PCR for Complement Receptor 1 Length Polymorphism Genotyping: An Innovative Tool for Alzheimer's Disease Gene Susceptibility Assessment
07:26

High-resolution Melting PCR for Complement Receptor 1 Length Polymorphism Genotyping: An Innovative Tool for Alzheimer's Disease Gene Susceptibility Assessment

Published on: July 18, 2017

Modulator-induced conformational changes in complement C5, implications for function and drug design.

Andrey Zhivnov1, Carolina Ottochian1, Karim El-Bouri2

  • 1Department of Life Sciences, University of Bath, Bath, United Kingdom.

Frontiers in Immunology
|June 1, 2026
PubMed
Summary
This summary is machine-generated.

Complement component C5 inhibitors achieve efficacy through diverse structural mechanisms, not just steric hindrance. Understanding these conformational changes enables rational design of novel complement therapeutics for autoimmune and inflammatory diseases.

Keywords:
C5 convertaseallosteric inhibition mechanismcomplement C5complement inhibitioninnate immunityprotein conformational analysis

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Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET
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Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET

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Area of Science:

  • Immunology
  • Structural Biology
  • Drug Discovery

Background:

  • The human complement system is vital for innate immunity, involving proteolytic cascades.
  • Complement component C5 (C5) cleavage generates effectors in autoimmune and inflammatory diseases.
  • Current C5 inhibitors target diverse sites, but their structural mechanisms are unclear.

Purpose of the Study:

  • To systematically compare the structural basis of C5 inhibition by various modulators.
  • To understand how distinct binding sites lead to comparable functional outcomes.
  • To provide a framework for designing next-generation complement therapeutics.

Main Methods:

  • Systematic comparison of twelve C5-modulator complexes.
  • Analysis of domain superposition, interface quantification, and conformational changes.
  • Rigid cluster decomposition and benchmarking against cobra venom factor (CVF).

Main Results:

  • Modulators induce conformational and dynamic changes beyond their binding sites.
  • The MG3 domain acts as a conformational relay; MG8 rigidity correlates with global constraint.
  • Inhibitors induce α-helical restructuring of the C5a scissile loop, but this is not universally required for blockade.
  • Complete inhibitors achieve efficacy via distinct structural rearrangements, not a single shared mechanism.

Conclusions:

  • C5 inhibition depends on conformational perturbation, not solely steric hindrance.
  • Distinct structural mechanisms underlie the efficacy of different C5 inhibitors.
  • Findings provide a structural basis for rational design of novel complement therapeutics.