12/28/2023 0 Comments Dank jotspot google sitesThis interaction could restrict the elbow angle to a maximum of 180°. The ball consists of conserved amino acid residues Phe148 and Pro149 in VH and the socket is formed by conserved amino acid residues Leu/Val11, Thr110, and Ser112 in the CH1 domain. This occurs in the HC at the interface between VH and CH1. An early analysis of the elbow motion in Fabs discovered a conserved feature that is referred to as a molecular ball-and-socket joint. This may result from the presence of an extra amino acid residue (usually a glycine) present in the switch region of λ LCs. Fabs with lambda (λ) light chains have a wider range of angles, indicating higher levels of flexibility. In an early survey of Fabs with kappa (κ) light chains, the angle was shown to vary from 116° to 226°. The orientation of the V domains with respect to the C domains is referred to as the elbow angle or elbow bend, which can vary significantly. The switch region, an extended polypeptide chain, connects the V and C domains. This is defined by the angle between the pseudo-two-fold axes relating the two pairs of domains (VH, VL and CH1, CL). The overall arrangement of the HC and LC domains of the Fab are characterized by what is called the elbow bend or elbow angle. The other isotypes are monomeric (a monomer is defined here as a pair of HC-LCs.). The IgA and IgM isotopes have an additional J-chain, which allows the formation of dimers and pentamers, respectively. IgEs and IgMs have one variable and four constant domains. IgAs, IgDs, and IgGs have three constant (C) and one variable (V) domains. In comparison, human antibody HCs can be one of five isotypes, IgA, IgD, IgE, IgG, and IgM, each with an independent role in the adaptive immune system. Both LC classes have two domains, a constant domain (CL) and a variable domain (VL). Human LCs can be one of two functionally similar classes, κ or λ. The two HCs of the heterotetramer are also linked by disulfide bridges. The HC and LC of the heterodimer are linked through disulfide bonds. In natural systems, the pairing of one LC with one HC associates with another identical heterodimer to form the intact immunoglobulin. Human immunoglobulins are Y-shaped proteins composed of two identical light chains (LCs) and two identical heavy chains (HCs). The overall structure of antibodies, including the folding pattern of the individual domains and basic features of the antigen-combining sites, has been the subject of several reviews. The structural data includes complexes of these molecules with proteins, other macromolecules, peptides, and haptens. At present, the Protein Data Bank (PDB) contains over 3500 structures of antibody fragments (Fabs, Fvs, scFvs, and Fcs), as well as a small number of intact antibody structures. Our knowledge of the three-dimensional structure of antibodies has emerged from crystallographic studies reported from numerous laboratories beginning in the 1970s. The engineering approaches being used are based on our knowledge of protein structure and, in particular, our knowledge of how the structures are linked to their function. Different strategies of preparing bispecific and multispecific molecules for an array of therapeutic applications are included.Ĭurrently, all antibodies and antibody-derived macromolecules being developed for a wide spectrum of therapeutic indications require protein engineering. We also review the design and selection of binding arms, and avidity modulation. The platforms examined include the development of antibodies, antibody fragments, bispecific antibody, and antibody fusion products, whose efficacy and manufacturability can be improved via humanization, affinity modulation, and stability enhancement. In this review, our basic understanding of the antibody structure is described along with how that knowledge has leveraged the engineering of antibody and antibody-related therapeutics having the appropriate antigen affinity, effector function, and biophysical properties. Our knowledge of the structure–function relationships of antibodies provides a platform for protein engineering that has been exploited to generate a wide range of biologics for a host of therapeutic indications. Antibodies and antibody-derived macromolecules have established themselves as the mainstay in protein-based therapeutic molecules (biologics).
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