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Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases

Bruton’s tyrosine kinase (BTK) is a critical component in B-cell receptor (BCR) signaling and is also expressed in haematogenic and innate immune cells. Inhibition of BTK hyperactivity is implicated in B-cell malignancies and autoimmune diseases. This review derives the structural complementarity of...

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Autores principales: Najmi, Asim, Thangavel, Neelaveni, Mohanan, Anugeetha Thacheril, Qadri, Marwa, Albratty, Mohammed, Ashraf, Safeena Eranhiyil, Saleh, Safaa Fathy, Nayeem, Maryam, Mohan, Syam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10051736/
https://www.ncbi.nlm.nih.gov/pubmed/36986499
http://dx.doi.org/10.3390/ph16030400
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author Najmi, Asim
Thangavel, Neelaveni
Mohanan, Anugeetha Thacheril
Qadri, Marwa
Albratty, Mohammed
Ashraf, Safeena Eranhiyil
Saleh, Safaa Fathy
Nayeem, Maryam
Mohan, Syam
author_facet Najmi, Asim
Thangavel, Neelaveni
Mohanan, Anugeetha Thacheril
Qadri, Marwa
Albratty, Mohammed
Ashraf, Safeena Eranhiyil
Saleh, Safaa Fathy
Nayeem, Maryam
Mohan, Syam
author_sort Najmi, Asim
collection PubMed
description Bruton’s tyrosine kinase (BTK) is a critical component in B-cell receptor (BCR) signaling and is also expressed in haematogenic and innate immune cells. Inhibition of BTK hyperactivity is implicated in B-cell malignancies and autoimmune diseases. This review derives the structural complementarity of the BTK-kinase domain and its inhibitors from recent three-dimensional structures of inhibitor-bound BTK in the protein data bank (PDB). Additionally, this review analyzes BTK-mediated effector responses of B-cell development and antibody production. Covalent inhibitors contain an α, β-unsaturated carbonyl moiety that forms a covalent bond with Cys481, stabilizing αC-helix in inactive-out conformation which inhibits Tyr551 autophosphorylation. Asn484, located two carbons far from Cys481, influences the stability of the BTK-transition complex. Non-covalent inhibitors engage the BTK-kinase domain through an induced-fit mechanism independent of Cys481 interaction and bind to Tyr551 in the activation kink resulting in H3 cleft, determining BTK selectivity. Covalent and non-covalent binding to the kinase domain of BTK shall induce conformational changes in other domains; therefore, investigating the whole-length BTK conformation is necessary to comprehend BTK’s autophosphorylation inhibition. Knowledge about the structural complementarity of BTK and its inhibitors supports the optimization of existing drugs and the discovery of drugs for implication in B-cell malignancies and autoimmune diseases.
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spelling pubmed-100517362023-03-30 Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases Najmi, Asim Thangavel, Neelaveni Mohanan, Anugeetha Thacheril Qadri, Marwa Albratty, Mohammed Ashraf, Safeena Eranhiyil Saleh, Safaa Fathy Nayeem, Maryam Mohan, Syam Pharmaceuticals (Basel) Review Bruton’s tyrosine kinase (BTK) is a critical component in B-cell receptor (BCR) signaling and is also expressed in haematogenic and innate immune cells. Inhibition of BTK hyperactivity is implicated in B-cell malignancies and autoimmune diseases. This review derives the structural complementarity of the BTK-kinase domain and its inhibitors from recent three-dimensional structures of inhibitor-bound BTK in the protein data bank (PDB). Additionally, this review analyzes BTK-mediated effector responses of B-cell development and antibody production. Covalent inhibitors contain an α, β-unsaturated carbonyl moiety that forms a covalent bond with Cys481, stabilizing αC-helix in inactive-out conformation which inhibits Tyr551 autophosphorylation. Asn484, located two carbons far from Cys481, influences the stability of the BTK-transition complex. Non-covalent inhibitors engage the BTK-kinase domain through an induced-fit mechanism independent of Cys481 interaction and bind to Tyr551 in the activation kink resulting in H3 cleft, determining BTK selectivity. Covalent and non-covalent binding to the kinase domain of BTK shall induce conformational changes in other domains; therefore, investigating the whole-length BTK conformation is necessary to comprehend BTK’s autophosphorylation inhibition. Knowledge about the structural complementarity of BTK and its inhibitors supports the optimization of existing drugs and the discovery of drugs for implication in B-cell malignancies and autoimmune diseases. MDPI 2023-03-07 /pmc/articles/PMC10051736/ /pubmed/36986499 http://dx.doi.org/10.3390/ph16030400 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Najmi, Asim
Thangavel, Neelaveni
Mohanan, Anugeetha Thacheril
Qadri, Marwa
Albratty, Mohammed
Ashraf, Safeena Eranhiyil
Saleh, Safaa Fathy
Nayeem, Maryam
Mohan, Syam
Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases
title Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases
title_full Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases
title_fullStr Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases
title_full_unstemmed Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases
title_short Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases
title_sort structural complementarity of bruton’s tyrosine kinase and its inhibitors for implication in b-cell malignancies and autoimmune diseases
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10051736/
https://www.ncbi.nlm.nih.gov/pubmed/36986499
http://dx.doi.org/10.3390/ph16030400
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