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Pay close attention to the information related to figure 3.14a and the structure of the PKA catalytic site in this figure.  In a few well-written sentences, propose the following: A mutation that would result in PKA becoming a dead kinase*. A mutation that would result in PKA becoming a constitutively active** kinase.

Pay close attention to the information related to figure 3.14a and the structure of the PKA catalytic site in this figure.  In a few well-written sentences, propose the following: A mutation that would result in PKA becoming a dead kinase*. A mutation that would result in PKA becoming a constitutively active** kinase.

Biochemistry
Biochemistry
9th Edition
ISBN:9781319114671
Author:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
Publisher:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
Chapter1: Biochemistry: An Evolving Science
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Pay close attention to the information related to figure 3.14a and the structure of the PKA catalytic site in this figure. 

  1. In a few well-written sentences, propose the following:
    1. A mutation that would result in PKA becoming a dead kinase*.
    2. A mutation that would result in PKA becoming a constitutively active** kinase.
PROTEIN KINASES 53 Figure 3.14 (а) The active site of protein kinases. (a) Key catalytic residues are contributed by both the N- and C-lobes, including Lys72 and Asp184, which help to coordinate the ATP, and Asp166 on the catalytic loop (orange), which acts as a general base to activate the substrate hydroxyl moiety. Proper positioning of these and other catalytic residues is dependent on tertiary interactions with key elements in the kinase structure, especially the C-helix (purple) in the N-lobe and the activation loop (green) in the C-lobe. In many kinases, the C-helix and activation loop are used as structural levers for controlling kinase activity. (b) Cyclin-dependent kinase (CDK) activation is regulated by proper positioning of the C-helix (purple) and the activation loop (green). Dramatic repositioning of the C-helix occurs upon cyclin binding, while proper positioning of the activation loop occurs upon activating phosphorylation of Thr197. Together, these conformational changes lead to proper assembly of the active site and clearance of the peptide-binding site. Numbering of key residues is based to their positions in the protein kinase A (PKA) sequence. (b, Adapted from M. Huse and J. Kuriyan, Cell 109:275–282, 2002. With permission from Elsevier.) N-lobe C-helix Lys72 Glu91 NH2 *NH3 substrate о—Р— о—р— о—Р. H он ОН Mg** O- Asp166 Asp184 catalytic loop NH H,N* NH2 Thr197 Arg165 C-lobe O- activation loop (b) C-helix in position Lys72 cyclin cyclin Glu91 Thr 197 cyclin activation loop in position Thr 197 inactive CDK phosphorylated CDK bound to cyclin CDK bound to cyclin describe these key conserved catalytic residues using the residue number- ing from cyclic AMP-activated protein kinase A (PKA), a Ser/Thr kinase that was one of the first protein kinases to be structurally characterized (Figure 3.14a); other individual kinases have diverse residue numbering (and different insertions and deletions within the catalytic domain). The N-terminal lobe contains residues that are primarily involved in ATP coordination. This includes the phosphate-binding loop (P-loop), which is a flexible glycine-rich segment. In addition, Lys72 plays a critical role in coordinating the negatively charged phosphate moieties of ATP. Many of the remaining critical catalytic residues are contained in the slightly larger C-terminal lobe. Asp166 lies within a segment known as the cata- lytic loop; this residue serves as the general base that abstracts the proton from the attacking substrate peptide hydroxyl group. Two other C-lobe residues, Asp184 and Asn171, play a critical role in ATP binding. 1 O=PIO ...... 0=PIO.
Transcribed Image Text:PROTEIN KINASES 53 Figure 3.14 (а) The active site of protein kinases. (a) Key catalytic residues are contributed by both the N- and C-lobes, including Lys72 and Asp184, which help to coordinate the ATP, and Asp166 on the catalytic loop (orange), which acts as a general base to activate the substrate hydroxyl moiety. Proper positioning of these and other catalytic residues is dependent on tertiary interactions with key elements in the kinase structure, especially the C-helix (purple) in the N-lobe and the activation loop (green) in the C-lobe. In many kinases, the C-helix and activation loop are used as structural levers for controlling kinase activity. (b) Cyclin-dependent kinase (CDK) activation is regulated by proper positioning of the C-helix (purple) and the activation loop (green). Dramatic repositioning of the C-helix occurs upon cyclin binding, while proper positioning of the activation loop occurs upon activating phosphorylation of Thr197. Together, these conformational changes lead to proper assembly of the active site and clearance of the peptide-binding site. Numbering of key residues is based to their positions in the protein kinase A (PKA) sequence. (b, Adapted from M. Huse and J. Kuriyan, Cell 109:275–282, 2002. With permission from Elsevier.) N-lobe C-helix Lys72 Glu91 NH2 *NH3 substrate о—Р— о—р— о—Р. H он ОН Mg** O- Asp166 Asp184 catalytic loop NH H,N* NH2 Thr197 Arg165 C-lobe O- activation loop (b) C-helix in position Lys72 cyclin cyclin Glu91 Thr 197 cyclin activation loop in position Thr 197 inactive CDK phosphorylated CDK bound to cyclin CDK bound to cyclin describe these key conserved catalytic residues using the residue number- ing from cyclic AMP-activated protein kinase A (PKA), a Ser/Thr kinase that was one of the first protein kinases to be structurally characterized (Figure 3.14a); other individual kinases have diverse residue numbering (and different insertions and deletions within the catalytic domain). The N-terminal lobe contains residues that are primarily involved in ATP coordination. This includes the phosphate-binding loop (P-loop), which is a flexible glycine-rich segment. In addition, Lys72 plays a critical role in coordinating the negatively charged phosphate moieties of ATP. Many of the remaining critical catalytic residues are contained in the slightly larger C-terminal lobe. Asp166 lies within a segment known as the cata- lytic loop; this residue serves as the general base that abstracts the proton from the attacking substrate peptide hydroxyl group. Two other C-lobe residues, Asp184 and Asn171, play a critical role in ATP binding. 1 O=PIO ...... 0=PIO.
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