Smooth Transitions
Tip #1: When developing a series of scenes illustrating related parts of a protein, use the “transition options” to create smooth transitions void of peculiar zoom-outs, etc.
Initial Scene (Reset)
The HMG binding pocket is the site of catalysis in HMGR. The “cis-loop” that bends over the top of HMG is a critical structural element of this binding site. Residues E559 and D767 and are positioned in the active site as is K691 which is only 2.7 angstroms from the HMG O2 carbonyl oxygen. It is this K691 that likely stabilizes the negatively charged oxygen of the first mevaldyl-CoA intermediate. The mevaldyl CoA intermediate is subsequently converted to Mavaldehyde with added stabilization from H866, which is within hydrogen bonding distance of the thiol group. It is then believed that the close proximity of E559 and D767 increases the pKA of E559, allowing it to be a proton donor for the reduction of mevaldehyde into mevalonate.
Compared with:
The HMG binding pocket is the site of catalysis in HMGR. The“cis-loop” that bends over the top of HMG is a critical structural element of this binding site. Residues E559 and D767 and are positioned in the active site as is K691 which is only 2.7 angstroms from the HMG O2 carbonyl oxygen...
Tip #2: It is best to establish a color scheme for all domains of interest and to stick with this color scheme throughout the analysis
Initial Scene (Reset)
The alpha-A helix of NSH2 (residues 340-345) is anchored into a cavity created by the C2 and Kinase domain interface. Helix α11K of the Kinase domain (residues 1017-1024) interacts with the alpha-A helix of nSH2. nSH2 interacts with the C2 domain through a network of charge-charge interactions involving two loops on nSH2 (Residues 374-377 & 350-354) and C2 residues 364-371, a strong salt bridge between NSH2 Glu 349 and C2 residue Arg 357, and hydrogen bonds between NSH2 Glu 348 and C2 Glu 453 and Asp 454.
Tip #3: Providing a wide view scene of an area of interest before zooming in provides context
Initial Scene (Reset)
This loop in the helical domain which contains the hotspots (residues 542-546) is located precisely where the phosphopeptide of NSH2 ligands, like PDGFR, bind to NSH2. The salt bridge formed between Glu 542 and nSH2 is disrupted upon binding phosphorylated peptides like PDGFR, eliminating nSH2-mediated inhibition of p110α and activating the enzyme to phosphorylate PIP2 into PIP3.
Tip #4: When switching focus to a new domain, it is best to zoom out and orient the reader to the new domain of interest
Initial Scene (Reset)
The alpha-A helix of NSH2 (residues 340-345) is anchored into a cavity created by the C2 and Kinase domain interface. Helix α11K of the Kinase domain (residues 1017-1024) interacts with the alpha-A helix of nSH2. nSH2 interacts with the C2 domain through a network of charge-charge interactions involving two loops on nSH2 (Residues 374-377 & 350-354) and C2 residues 364-371, a strong salt bridge between NSH2 Glu 349 and C2 residue Arg 357, and hydrogen bonds between NSH2 Glu 348 and C2 Glu 453 and Asp 454.
Tip #5: Eliminate the Scene transition when comparing different binding interactions for similar ligands
Initial Scene (Reset)
LY294002, a competitive inhibitor of ATP binding in the PI3K kinase domain, was first discovered by scientists at Eli Lilly. Quercetin, Myricetin & Staurosporine are natural compounds which broadly inhibit protein kinases. Understanding how ATP binds to the ATP binding site within the kinase domain of PI3Kγ and how various inhibitors prevent this interaction helps elucidate ways to develop effective, selective inhibitors. See p110γ bound to ATP (1e8x), Wortmannin (1e7u), LY294002 (1e7v), Quercetin (1e8w), Staurosporine (1e8z), Myricetin (1e90).
