Your browser doesn't support javascript.
Differential impact of BTK active site inhibitors on the conformational state of full-length BTK.
Joseph, Raji E; Amatya, Neha; Fulton, D Bruce; Engen, John R; Wales, Thomas E; Andreotti, Amy.
  • Joseph RE; Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States.
  • Amatya N; Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States.
  • Fulton DB; Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States.
  • Engen JR; Department of Chemistry and Chemical Biology, Northeastern University, Boston, United States.
  • Wales TE; Department of Chemistry and Chemical Biology, Northeastern University, Boston, United States.
  • Andreotti A; Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States.
Elife ; 92020 11 23.
Article in English | MEDLINE | ID: covidwho-940328
Semantic information from SemMedBD (by NLM)
1. Inhibitor PART_OF Agammaglobulinaemia tyrosine kinase
Subject
Inhibitor
Predicate
PART_OF
Object
Agammaglobulinaemia tyrosine kinase
2. drug binding CAUSES enzyme activity
Subject
drug binding
Predicate
CAUSES
Object
enzyme activity
3. Inhibitor PART_OF Agammaglobulinaemia tyrosine kinase
Subject
Inhibitor
Predicate
PART_OF
Object
Agammaglobulinaemia tyrosine kinase
4. drug binding CAUSES enzyme activity
Subject
drug binding
Predicate
CAUSES
Object
enzyme activity
ABSTRACT
Bruton's tyrosine kinase (BTK) is targeted in the treatment of B-cell disorders including leukemias and lymphomas. Currently approved BTK inhibitors, including Ibrutinib, a first-in-class covalent inhibitor of BTK, bind directly to the kinase active site. While effective at blocking the catalytic activity of BTK, consequences of drug binding on the global conformation of full-length BTK are unknown. Here, we uncover a range of conformational effects in full-length BTK induced by a panel of active site inhibitors, including large-scale shifts in the conformational equilibria of the regulatory domains. Additionally, we find that a remote Ibrutinib resistance mutation, T316A in the BTK SH2 domain, drives spurious BTK activity by destabilizing the compact autoinhibitory conformation of full-length BTK, shifting the conformational ensemble away from the autoinhibited form. Future development of BTK inhibitors will need to consider long-range allosteric consequences of inhibitor binding, including the emerging application of these BTK inhibitors in treating COVID-19.
Treatments for blood cancers, such as leukemia and lymphoma, rely heavily on chemotherapy, using drugs that target a vulnerable aspect of the cancer cells. B-cells, a type of white blood cell that produces antibodies, require a protein called Bruton's tyrosine kinase, or BTK for short, to survive. The drug ibrutinib (Imbruvica) is used to treat B-cell cancers by blocking BTK. The BTK protein consists of several regions. One of them, known as the kinase domain, is responsible for its activity as an enzyme (which allows it to modify other proteins by adding a 'tag' known as a phosphate group). The other regions of BTK, known as regulatory modules, control this activity. In BTK's inactive form, the regulatory modules attach to the kinase domain, blocking the regulatory modules from interacting with other proteins. When BTK is activated, it changes its conformation so the regulatory regions detach and become available for interactions with other proteins, at the same time exposing the active kinase domain. Ibrutinib and other BTK drugs in development bind to the kinase domain to block its activity. However, it is not known how this binding affects the regulatory modules. Previous efforts to study how drugs bind to BTK have used a version of the protein that only had the kinase domain, instead of the full-length protein. Now, Joseph et al. have studied full-length BTK and how it binds to five different drugs. The results reveal that ibrutinib and another drug called dasatinib both indirectly disrupt the normal position of the regulatory domains pushing BTK toward a conformation that resembles the activated state. By contrast, the three other compounds studied do not affect the inactive structure. Joseph et al. also examined a mutation in BTK that confers resistance against ibrutinib. This mutation increases the activity of BTK by disrupting the inactive structure, leading to B cells surviving better. Understanding how drug resistance mechanisms can work will lead to better drug treatment strategies for cancer. BTK is also a target in other diseases such as allergies or asthma and even COVID-19. If interactions between partner proteins and the regulatory domain are important in these diseases, then they may be better treated with drugs that maintain the regulatory modules in their inactive state. This research will help to design drugs that are better able to control BTK activity.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Protein Conformation / Catalytic Domain / Protein Kinase Inhibitors / Agammaglobulinaemia Tyrosine Kinase Type of study: Experimental Studies / Prognostic study Limits: Humans Language: English Year: 2020 Document Type: Article Affiliation country: ELife.60470

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: Protein Conformation / Catalytic Domain / Protein Kinase Inhibitors / Agammaglobulinaemia Tyrosine Kinase Type of study: Experimental Studies / Prognostic study Limits: Humans Language: English Year: 2020 Document Type: Article Affiliation country: ELife.60470