Stereochemical course of the phospho group transfer catalyzed by cAMP-dependent protein kinase

Ho, Mengfei; Bramson, H. Neal; Hansen, David E.; Knowles, Jeremy R.; Kaiser, E. T.

doi:10.1021/ja00216a068

Cited by 71 publications

(45 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(1)), should be formed before the phosphoryl transfer step [2,13]. Secondly, it was suggested that the inhibitor I may bind with the free enzyme (E) and with the enzyme-substrate complexes EA and EB, as shown in Fig.…”

Section: Kinetic Formalismmentioning

confidence: 99%

See 1 more Smart Citation

Allosteric Cooperativity in Inhibition of Protein Kinase a Catalytic Subunit

Kuznetsov¹,

Järv²

2008

TOEIJ

View full text Add to dashboard Cite

Allosteric cooperativity in inhibition of protein kinase A was studied for the first time kinetically, by using the second-order rate constants of kemptide phosphorylation, measured in the absence and presence of inhibitors, and the effect of cooperativity was characterized in terms of the interaction factor . This kinetic method was evaluated for differently targeted inhibitors H89 and LRRAALG-NH 2 , and interaction of these compounds with the free enzyme and the enzyme-substrate complexes was quantified. The inhibitory effect of these compounds was asymmetric relatively ATP and kemptide, and allosteric enhancement of LRRAALG-NH 2 binding in the presence of ATP was revealed. This cooperative effect was compared with results of ligand binding studies and the principle "better binding -stronger allostery" was formulated and formalized in terms of a linear-free-energy relationship p( ) = C + S pK i , where p( ) stands for the negative logarithm of the interaction factor and pK i characterizes affinity of the free enzyme for the inhibitory peptide, C=-2.7 and S=0.9, r=0.92.

show abstract

Section: Kinetic Formalismmentioning

confidence: 99%

“…The reaction catalyzed by these enzymes involves two substrates -the phosphorylatable protein or peptide and ATP as the source of the phosphoryl group. This phosphoryl group is directly transferred between the enzyme-bound substrates [2].…”

Section: Introductionmentioning

confidence: 99%

Allosteric Cooperativity in Inhibition of Protein Kinase a Catalytic Subunit

Kuznetsov¹,

Järv²

2008

TOEIJ

View full text Add to dashboard Cite

show abstract

“…The catalytic core of the large protein kinase family contains 9 invariant and 15 highly conserved residues involved in ATP binding and catalysis (14)(15)(16) (23).…”

Section: Introductionmentioning

confidence: 99%

“…Together with murine Tec and Itk/Tsk it forms a new family ofcytoplasmic PTKs (4-7). The two point mutations reported to cause XLA have both been found in the kinase domain (2), whereas the murine X-linked immunodeficiency defect represents the first missense mutation (8, 9) in the recently identified pleckstrin homology region located in the N terminus of BTK (10-13).The catalytic core of the large protein kinase family contains 9 invariant and 15 highly conserved residues involved in ATP binding and catalysis (14)(15)(16) (23).The x-ray structures, including the independently solved ternary complex (24), provide a comprehensive description of the enzyme, which has been used in modeling of myosin light chain kinase (25), cell division cycle 2 (CDC2) protein kinase (26), and epidermal growth factor receptor PTK (27). The crystal structures of the human cyclin-dependent kinase 2 (CDK2) (28) and mitogen-activated protein (MAP) kinase ERK2 (extracellular signal-related kinase 2) (29) have the same overall fold as cAPK, suggesting that the kinase homology models are valid.…”

mentioning

confidence: 99%

“…The first crystal structure of a protein kinase was the binary complex of the catalytic subunit of cAMP-dependent protein kinase [cAPK; a proteinserine/threonine kinase (PSK)] with a specific protein kinase inhibitor, PKI (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) (17,18), subsequently refined to 2.0 A (19). The binary complex and the ternary complex with PKI (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) and MnATP (20) have a closed conformation, whereas the mammalian binary complex has an open conformation in which the upper domain is displaced 150 with respect to the lower domain (21). Structures of substrate and product peptides complexed with the enzyme (22) support a direct in-line mechanism …”

mentioning

confidence: 99%

See 1 more Smart Citation

Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease.

Vihinen

Vetrie

Maniar

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

X-linked agammaglobulinemia (XLA) is a hereditary defect of B-cell differentiation in man caused by deficiency of Bruton tyrosine kinase (BTK). A three-dimensional model for the BTK kinase domain, based on the core structure of cAMP-dependent protein kinase, was used to interpret the structural basis for disease in eight independent point mutations in patients with XLA. As Arg-525 of BTK has been thought to functionally substitute for a critical lysine residue in proteinserine kinases, the mutation Arg-525 -* Gln was studied and found to abrogate the tyrosine kinase activity of BTK. All of the eight mutations Glu, Arg-520 -+ Glu, Arg-525 --Gln, Arg-562 -+ Pro, Ala-582 --Val, Glu-589 --Gly, Gly-594 --Glu, and Gly-613-* Asp) were located on one face ofthe BTK kinase domain, indicating structural clustering of functionally important residues. X-linked agammaglobulinemia (XLA) is a human immunodeficiency disease characterized by a lymphocyte differentiation block that results in a deficiency of B cells and immunoglobulins, leading to increased susceptibility to infections (1). Recently, the gene mutated in XLA was shown to encode a cytoplasmic protein-tyrosine kinase (PTK) designated Bruton XLA tyrosine kinase (BTK; formerly ATK or BPK) (2, 3). XLA is thus the first Mendelian disease in which a cytoplasmic PTK was found to be mutated. BTK has a single kinase domain (also designated Src homology 1 [SH1] domain) and SH2 and SH3 domains, but lacks both an N-terminal consensus myristoylation sequence and a C-terminal regulatory region. Together with murine Tec and Itk/Tsk it forms a new family ofcytoplasmic PTKs (4-7). The two point mutations reported to cause XLA have both been found in the kinase domain (2), whereas the murine X-linked immunodeficiency defect represents the first missense mutation (8, 9) in the recently identified pleckstrin homology region located in the N terminus of BTK (10-13).The catalytic core of the large protein kinase family contains 9 invariant and 15 highly conserved residues involved in ATP binding and catalysis (14)(15)(16) (23).The x-ray structures, including the independently solved ternary complex (24), provide a comprehensive description of the enzyme, which has been used in modeling of myosin light chain kinase (25), cell division cycle 2 (CDC2) protein kinase (26), and epidermal growth factor receptor PTK (27). The crystal structures of the human cyclin-dependent kinase 2 (CDK2) (28) and mitogen-activated protein (MAP) kinase ERK2 (extracellular signal-related kinase 2) (29) have the same overall fold as cAPK, suggesting that the kinase homology models are valid.In addition to the previously known point mutations in XLA (Lys-430 -* Glu and Arg-525 --Gln) (2), six new missense mutations were found in this disease: Arg-520 -)Glu, Arg-562 -* Pro, Ala-582 -* Val, Gly, Gly-594 --Glu, and Gly-613 --Asp. The functional implications of these mutants were investigated in structural terms by modeling the BTK structure to provide the first three-dimensional model of a cytoplasmic PTK...

show abstract

Protein Kinase Inhibitors in Drug Discovery

Parang

Sun

2010

Pharmaceutical Sciences Encyclopedia

View full text Add to dashboard Cite

Protein kinases (PKs) have essential roles in cell‐signaling pathways by interacting with extracellular ligands such as growth factors and hormones and transmitting signals across the cell membrane to the cytoplasm and the nucleus. It is important to understand the mechanistic features of the particular target kinase when designing protein kinase inhibitors (PKIs). This chapter focuses on inhibitors directed against critical molecular targets that are approved or are in clinical trials.

show abstract

Stereochemical course of the phospho group transfer catalyzed by cAMP-dependent protein kinase

Cited by 71 publications

References 0 publications

Allosteric Cooperativity in Inhibition of Protein Kinase a Catalytic Subunit

Allosteric Cooperativity in Inhibition of Protein Kinase a Catalytic Subunit

Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease.

Protein Kinase Inhibitors in Drug Discovery

Contact Info

Product

Resources

About