Protein kinases — structure and function

Abstract

The solution of crystal structures from half a dozen protein kinases during the last four years in different laboratories has deepened our understanding of the catalysis and regulation of this enzyme class, and given a vigorous impetus to the whole field. Due to the great degree of sequence conservation among protein kinases the informational yield with every new structure is high, as each is a representative of the enzyme family in general and most often of a subclass in particular. This review will focus on the active site structure of cAMP-dependent protein kinase (cAPK) with special regard to two new crystal structures; one of an active protein kinase CKI*, which may represent an as yet unsolved step in the kinetic pathway, and the other of the insulin receptor kinase domain, the first structure of a tyrosine kinase.

Interaction of the Interferon-Induced PKR Protein Kinase with Inhibitory Proteins P58IPKand Vaccinia Virus K3L Is Mediated by Unique Domains: Implications for Kinase Regulation

“…Similarly, the LFIQME motif was not essential for P58 IPK -PKR interactions. On the basis of the crystal structures of various eukaryotic protein kinases, PKR aa 367 to 551 localize to within the large lobe of the generalized three-dimensional structure predicted for the PKR protein kinase catalytic domain, while aa 244 to 296 occupy a distinct region of the small lobe involved in nucleotide binding (10,74) and autophosphorylation. The large lobe of the eukaryotic protein kinase catalytic domain is largely responsible for substrate recognition and binding, although certain conserved residues contribute to nucleotide binding as well (74).…”

“…Thus, to this point, all BD-P58 IPK wt-interacting constructs of AD-PKR shared 52 aa in this region (aa 244 to 296). This region of PKR includes the nucleotide-binding domain essential for protein kinase activity (protein kinase catalytic domain conservation regions I and II [reviewed in reference 28]), including the glycine-rich domain and the invariant lysine residue which cooperatively participate in binding ATP (9,10,74). In addition, this region contains a potential site of autophosphorylation, threonine 258, critical for kinase activation (57).…”

“…However, unlike P58 IPK , which associates with structures within protein kinase catalytic domain homology region II (PKR aa 244 to 296), the K3L interactive region of PKR broadly maps to a nonoverlapping domain within the carboxyl-terminal 184 aa, corresponding to protein kinase catalytic domain homology regions VI to XI (28), which are predicted to participate in substrate recognition and binding (10,28,74). P58 IPK can self-associate in vivo.…”

Theoretical Studies of the Catalytic Mechanism of the Dihydroxyacetone Kinase

“…Members of protein kinase family has a significant common feature which is the sharing of a highly conserved catalytic center, as indicated above. 49,52,[64][65][66] This characteristic makes possible that one inhibitor molecule can bind to several kinases, preventing from the usual signaling needed for normal cellular behavior. However, it may be also feasible that the capability of interfering in a multitude of kinases is beneficial in cancer treatments, provided that the inhibitor is specific to cancerous cells.…”

Obtenção das quinases dependentes de ciclinas CDK9 e CDK11 humanas utilizando um sistema bacteriano de expressão (E. coli)

“…No sítio de ligação ao ATP em uma PK, a adenina ocupa a região mais profunda da fenda, de forma que o grupo trifosfato fica orientado para o exterior. O fosfato γ γ γ γ (terminal) da cadeia trifosfato situa-se próximo à superfície da enzima, bem ao lado do sítio de ligação ao substrato proteico aceptor de fosforila (BOSSEMEYER, 1995;HANKS et al, 1995 (BOSSEMEYER, 1995;HANKS et al, 1995). …”