Structural and thermodynamic insights into antibody light chain tetramer formation through 3D domain swapping

Sakai, Takahiro; Mashima, Tsuyoshi; Kobayashi, Naoya; Ogata, Hideaki; Duan, Lian; Fujiki, Ryo; Hengphasatporn, Kowit; Uda, Taizo; Shigeta, Yasuteru; Hifumi, Emi; Hirota, Shun

doi:10.1038/s41467-023-43443-4

Cited by 4 publications

(1 citation statement)

References 53 publications

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“…Structural ensemble analysis is one of the main applications of RING. It is commonly used to analyze molecular dynamics simulations by calculating probabilistic contact networks ( 12 , 13 ), and to analyze protein stability and perform virtual screening ( 14 , 15 ).…”

Section: Introductionmentioning

confidence: 99%

RING 4.0: faster residue interaction networks with novel interaction types across over 35,000 different chemical structures

Del Conte,

Camagni,

Clementel

et al. 2024

Nucleic Acids Research

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Residue interaction networks (RINs) are a valuable approach for representing contacts in protein structures. RINs have been widely used in various research areas, including the analysis of mutation effects, domain-domain communication, catalytic activity, and molecular dynamics simulations. The RING server is a powerful tool to calculate non-covalent molecular interactions based on geometrical parameters, providing high-quality and reliable results. Here, we introduce RING 4.0, which includes significant enhancements for identifying both covalent and non-covalent bonds in protein structures. It now encompasses seven different interaction types, with the addition of π-hydrogen, halogen bonds and metal ion coordination sites. The definitions of all available bond types have also been refined and RING can now process the complete PDB chemical component dictionary (over 35000 different molecules) which provides atom names and covalent connectivity information for all known ligands. Optimization of the software has improved execution time by an order of magnitude. The RING web server has been redesigned to provide a more engaging and interactive user experience, incorporating new visualization tools. Users can now visualize all types of interactions simultaneously in the structure viewer and network component. The web server, including extensive help and tutorials, is available from URL: https://ring.biocomputingup.it/.

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Section: Introductionmentioning

confidence: 99%

RING 4.0: faster residue interaction networks with novel interaction types across over 35,000 different chemical structures

Del Conte,

Camagni,

Clementel

et al. 2024

Nucleic Acids Research

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Conserved proline residues prevent dimerization and aggregation in the β‐lactamase BlaC

Chikunova,

Manley,

Heijjer

et al. 2024

Protein Science

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Evolution leads to conservation of amino acid residues in protein families. Conserved proline residues are usually considered to ensure the correct folding and to stabilize the three‐dimensional structure. Surprisingly, proline residues that are highly conserved in class A β‐lactamases were found to tolerate various substitutions without large losses in enzyme activity. We investigated the roles of three conserved prolines at positions 107, 226, and 258 in the β‐lactamase BlaC from Mycobacterium tuberculosis and found that mutations can lead to dimerization of the enzyme and an overall less stable protein that is prone to aggregate over time. For the variant Pro107Thr, the crystal structure shows dimer formation resembling domain swapping. It is concluded that the proline substitutions loosen the structure, enhancing multimerization. Even though the enzyme does not lose its properties without the conserved proline residues, the prolines ensure the long‐term structural integrity of the enzyme.

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Experimental and Computational Studies on Domain-Swapped Structure Stabilization of an Antibody Light Chain by Disulfide Bond Introduction

Fitriana,

Sakai,

Duan

et al. 2024

J. Med. Chem.

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Development of different platforms would be useful for designing functional antibodies to improve the efficiency of antibody-based drugs. Threedimensional domain swapping (3D-DS) may occur in the variable region of antibody light chain #4C214A, and a pair of domain-swapped dimers may interact with each other to form a tetramer. In this study, to stabilize the 3D-DS dimer structure in #4C214A, Val2 in strand A (swapping region) and Thr97 in strand G were replaced with Cys residues, generating #4 V2C/T97C/C214A with a Cys2− Cys97 disulfide bond that cross-links strands A and G of different protomers. The #4 V2C/T97C/C214A tetramer did not dissociate into monomers at low protein concentration (6 μM); however, some of the tetramers were converted to monomers by disulfide bond reduction. Two-dimensional free energy profile analysis for the tetramerization of two 3D-DS dimers was performed by molecular dynamics simulation. These results show that disulfide bond introduction is useful for controlling the dimerization/dissociation of the variable region through 3D-DS.

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Structural and thermodynamic insights into antibody light chain tetramer formation through 3D domain swapping

Cited by 4 publications

References 53 publications

RING 4.0: faster residue interaction networks with novel interaction types across over 35,000 different chemical structures

RING 4.0: faster residue interaction networks with novel interaction types across over 35,000 different chemical structures

Conserved proline residues prevent dimerization and aggregation in the β‐lactamase BlaC

Experimental and Computational Studies on Domain-Swapped Structure Stabilization of an Antibody Light Chain by Disulfide Bond Introduction

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