1. Volume 3, Issue 5, Pages 639-648 (May 1999)
Crystal Structure of Hck in Complex with a Src Family–Selective Tyrosine Kinase Inhibitor 
Thomas Schindler, Frank Sicheri, Alexander Pico, Aviv Gazit, Alexander Levitzki, John Kuriyan 
Molecular Cell 
Volume 3, Issue 5, Pages (May 1999)
DOI: /S (00)

2. Figure 1 Overview of the Hck–PP1 Complex
(A) Ribbon representation of the Hck structure. PP1, Tyr-416, and Tyr-527 are shown as stick figures. All ribbon diagrams were generated using RIBBONS (Carson 1991).
(B) Schematic representation of the domain organization in Src family tyrosine kinases. A myristoylated N-terminal region is followed by a “unique” region (U), which is not conserved between different members of the Src family. The SH2 and SH3 domains are separated from the catalytic domain (Y-kinase) by a linker (L). The catalytic segment (CS) and activation segment (AS) are indicated within the catalytic domain. The inactive form of the Src kinases is phosphorylated at Tyr-527, but not at Tyr-416 in the activation segment.
Molecular Cell 1999 3, DOI: ( /S (00) )

3. Figure 2 Electron Density for the Activation Segment of Hck
(A) Stereo diagram of electron density calculated using σA-weighted coefficients (Read 1986) of the form (2|Fo| − |Fc|) exp(iαc) and contoured at 1.0/2.0 σ, based on the molecular model and X-ray data for the Hck–PP1 complex described in this paper.
(B) Stereo diagram of difference electron density calculated using σA-weighted coefficients of the form (|Fo| − |Fc|) exp(iαc), where the observed and calculated structure factors, |Fo| and |Fc|, and the calculated phase, αc, are obtained from the original analysis of wild-type Hck complexed to AMP–PNP, at a resolution of 2.6/2.9 Å (Sicheri et al. 1997). The structural model shown, however, is that of the Hck–PP1 complex. The electron density contours are at 1σ (blue) and 2σ (red). This figure was prepared with BOBSCRIPT (Esnouf 1997).
Molecular Cell 1999 3, DOI: ( /S (00) )

4. Figure 3 The Activation Segment of Hck Blocks Peptide Binding
(A) Ribbon representation of the activation segment in the downregulated form of Hck. The polypeptide backbone of the catalytic domain is shown in blue, and that of the catalytic and activation segments are shown in green and magenta, respectively. Hydrogen-bonding interactions are depicted by dashed lines, and two water molecules are represented as red spheres.
(B) The region in the vicinity of Tyr-416 is shown. Superimposed in gray is the peptide substrate, as seen in the structure of insulin receptor tyrosine kinase complexed with a peptide substrate (PDB code 1ir3; Hubbard 1997). The figure was generated by superimposing the catalytic segments of the two kinases. PP1, Tyr-416, and the tyrosine residue in the peptide substrate are drawn as stick figures.
(C) Conformation of the activation segment in the inactivated form of Hck compared to its conformation in the fully active form of Lck (PDB code 3lck; Yamaguchi and Hendrickson 1996). The molecular surfaces of the catalytic domains, excluding the activation segment, are shown in gray. The figures in (B) and (C) were generated using the program GRASP (Nicholls et al. 1991).
Molecular Cell 1999 3, DOI: ( /S (00) )

5. Figure 4
Interdependence of the Conformations of Helix αC and the Activation Segment
The catalytic domain of inactive Hck is shown superimposed on that of active Lck (Yamaguchi and Hendrickson 1996) (A) and of inactive Cdk2 (B) (De Bondt et al. 1993). The structural alignments are based on the C-terminal lobe in (A) and on the β strands in the N-terminal lobe of the kinase domains in (B). Helix αC (α1 in Cdk2) and the activation segment are colored in blue, red, and green for Hck, Lck, and Cdk2, respectively. The figure was generated using RIBBONS (Carson 1991).
Molecular Cell 1999 3, DOI: ( /S (00) )

6. Figure 5 The Binding of PP1 to Hck
(A) Comparison of the structural formula of PP1 and adenosine.
(B) The structure of PP1 bound to Hck. The polypeptide backbone of the activation segment is shown in magenta. PP1 and selected residues of Hck are drawn as stick figures. Hydrogen-bonding interactions are depicted by dashed lines. A water molecule coordinated by Lys-295 and the ring nitrogen at position 6 in PP1 is represented as a red sphere. A stick representation of AMP–PNP as found in the previous structure of Hck (Sicheri et al. 1997) is superimposed in magenta. The two Hck structures were aligned on the basis of the catalytic segments in order to position the AMP–PNP in this figure.
Molecular Cell 1999 3, DOI: ( /S (00) )

7. Figure 6 Selectivity Determinants of PP1 Binding
(A) PP1 binding in Hck. Cα traces of the catalytic and activation segment are shown in green and magenta, respectively. Superimposed is the molecular surface of the binding site, in transparent gray. PP1 and selected residues of Hck are drawn as stick figures.
(B) PP1 modeled into the ATP-binding site of PKA (PDB code 1atp; Zheng et al. 1993). The model was generated by aligning the pyrazolo-pyrimidine moiety of PP1 and the adenine ring of ATP.
(C) Sequence comparison of Src family tyrosine kinase members with a set of other protein kinases. The inhibition constants (IC50) for PP1 were taken from Hanke et al ([†] PP1 was reported to be essentially inactive for inhibition of PKA). Thr-338 (*) and Ala 403 (#) are indicated in (A), as are the structurally equivalent residues in PKA, in (B).
Molecular Cell 1999 3, DOI: ( /S (00) )

8. Figure 7 PP1 Leaves Unfilled a Cavity in Inactive Hck
(A) Structure of the PP1-binding region in inactive Hck. PP1 binding creates a cavity (yellow surface) in the back of the ATP-binding site, where two well-ordered water molecules (W1 and W2) are found.
(B) The same cavity (yellow) viewed from the top of the N-terminal lobe of the catalytic domain. The collapse of this cavity in active Lck is indicated by showing helix αC as found in the structure of Lck (PDB code 3lck; Yamaguchi and Hendrickson 1996), drawn in orange.
Molecular Cell 1999 3, DOI: ( /S (00) )