Top Med Chem (2021) 36: 1–24
https://doi.org/10.1007/7355_2020_97
© Springer Nature Switzerland AG 2020
Published online: 6 May 2020
Function, Structure and Topology
of Protein Kinases
Sandra Röhm, Andreas Krämer, and Stefan Knapp
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 The Kinase Active State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3 Mechanism of Kinase Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 6
3.1 Kinase Activation by Interacting Domains and Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4 Canonical Type-I and Type-II Inhibitor Binding Mode . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.1 Noncanonical Binding Modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4.2 Allosteric Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
5 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Abstract Protein kinases represent one of the most successful target classes
for the development of new medicines. Because of their key roles in cellular
signalling, kinases are stringently regulated by a large diversity of mechanisms
such as post-translational modifications, interacting domains and proteins and
cellular localization. The high plasticity of protein kinases has been exploited for
the development of new inhibitor types such as type-II and type-I½ inhibitors
targeting inactive states of the kinase catalytic domain and allosteric inhibitors
that target induced binding pockets either adjacent (type-III) or distantly located
(type-IV) to the kinase ATP-binding site. Here we discuss structural elements of the
kinase active site, key mechanisms of kinase regulation and how these mechanisms
can be exploited for the development of selective kinase inhibitors.
Keywords Allosteric inhibitors, Kinase activation, Kinase regulation,
Structure-based drug design
S. Röhm, A. Krämer, and S. Knapp (*)
Johann Wolfgang Goethe-University, Institute for Pharmaceutical Chemistry, Frankfurt,
Germany
Johann Wolfgang Goethe-University, Buchmann Institute for Life Sciences, Frankfurt,
Germany
e-mail: knapp@pharmchem.uni-frankfurt.de
https://doi.org/10.1007/7355_2020_97
© Springer Nature Switzerland AG 2020
Published online: 6 May 2020
Function, Structure and Topology
of Protein Kinases
Sandra Röhm, Andreas Krämer, and Stefan Knapp
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 The Kinase Active State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3 Mechanism of Kinase Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 6
3.1 Kinase Activation by Interacting Domains and Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4 Canonical Type-I and Type-II Inhibitor Binding Mode . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.1 Noncanonical Binding Modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4.2 Allosteric Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
5 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Abstract Protein kinases represent one of the most successful target classes
for the development of new medicines. Because of their key roles in cellular
signalling, kinases are stringently regulated by a large diversity of mechanisms
such as post-translational modifications, interacting domains and proteins and
cellular localization. The high plasticity of protein kinases has been exploited for
the development of new inhibitor types such as type-II and type-I½ inhibitors
targeting inactive states of the kinase catalytic domain and allosteric inhibitors
that target induced binding pockets either adjacent (type-III) or distantly located
(type-IV) to the kinase ATP-binding site. Here we discuss structural elements of the
kinase active site, key mechanisms of kinase regulation and how these mechanisms
can be exploited for the development of selective kinase inhibitors.
Keywords Allosteric inhibitors, Kinase activation, Kinase regulation,
Structure-based drug design
S. Röhm, A. Krämer, and S. Knapp (*)
Johann Wolfgang Goethe-University, Institute for Pharmaceutical Chemistry, Frankfurt,
Germany
Johann Wolfgang Goethe-University, Buchmann Institute for Life Sciences, Frankfurt,
Germany
e-mail: knapp@pharmchem.uni-frankfurt.de