Click Next to continue. [END TEXT] [END] [START AUTODELAY=15] [COMMANDS] open 1cqe_edit.pdb; open 6cox_edit.pdb; modelcolor cyan #0; modelcolor magenta #1; window; linewidth 2; scale 1.7; move x -1; wait [END COMMANDS] [UNDO] close #0; close #1 [END UNDO] [TEXT] COX synthesizes prostaglandins, which mediate several functions in the body. The COX-1 isoform (cyan) contributes to many beneficial functions (for example, protecting the lining of the stomach), but the COX-2 isoform (magenta) has been implicated in pain and inflammation. Thus, it may be useful to inhibit COX-2 more than COX-1. Although COX functions as a homodimer, we will compare monomers (each monomer contains a complete active site). [END TEXT] [END] [START] [COMMANDS] ~disp; ribrepr sharp; ribbon [END COMMANDS] [UNDO] ~ribbon; disp [END UNDO] [TEXT] COX-1 and COX-2 are shown as ribbons.
Their sequences are about 60% identical and their structures are very similar. [END TEXT] [END] [START] [COMMANDS] surfcat ligs :flp,s58; colordef newblue 0 0.2 1.0 disp :flp,s58; color newblue :flp; color red :s58; surf ligs; surfrepr mesh; set independent; turn y 2 180; wait; ~set independent [END COMMANDS] [UNDO] ~surf; ~disp :flp,s58; color cyan #0; color magenta #1 [END UNDO] [TEXT] Bound inhibitors are shown with mesh surfaces. The nonselective inhibitor flurbiprofen (blue) is bound to COX-1, and the COX-2-selective inhibitor SC-558 (red) is bound to COX-2. [END TEXT] [END] [START] [COMMANDS] ~select 0; move x -60; wait; select 0; move x 2 15; wait; scale 1.05 6; wait [END COMMANDS] [UNDO] [END UNDO] [TEXT] Superimposing COX-1 and COX-2 further illustrates their high similarity. [END TEXT] [END] [START] [COMMANDS] disp :434.a,518.a,523.a & with CA/C1'; repr stick; repr bs @ca; ~ribbon; window; wait; scale 1.05 8; wait [END COMMANDS] [UNDO] ~disp :434.a,518.a,523.a; repr wire; ribbon [END UNDO] [TEXT] Now just the inhibitors and a few side chains that contribute to differences in the active site are shown. Alpha-carbons are drawn as balls.
Although the middle residue is the same type in the two isoforms, the residues on either side are larger in COX-1 (cyan) than in COX-2 (magenta). One of these residues pushes the middle residue toward the active site. [END TEXT] [END] [START] [COMMANDS] repr sphere :434.a,518.a,523.a [END COMMANDS] [TEXT] A sphere representation of the same side chains gives a better sense of their volume.
Click to view the side chains as: sticks spheres[END TEXT] [UNDO] repr stick :434.a,518.a,523.a; repr bs @ca [END UNDO] [END] [START] [COMMANDS] repr sphere :434.a,518.a,523.a; ~disp #0:434.a,518.a,523.a; ~disp :flp; ~surf :flp; turn x -1 40; wait [END COMMANDS] [TEXT] The inhibitor SC-558 (red) is COX-2-selective because it can fit in the COX-2 site (magenta residues)... [END TEXT] [UNDO] disp #0:434.a,518.a,523.a & with CA/C1'; disp :flp; surf :flp [END UNDO] [END] [START] [COMMANDS] disp #0:434.a,518.a,523.a & with CA/C1'; ~disp #1:434.a,518.a,523.a; turn y 1 40; wait [END COMMANDS] [TEXT] ...but is crowded out of the COX-1 site (cyan residues).
Click to view: COX-1 residues COX-2 residues both sets[END TEXT] [UNDO] ~disp #0:434.a,518.a,523.a; disp #1:434.a,518.a,523.a & with CA/C1' [END UNDO] [END] [START] [COMMANDS] disp :434.a,518.a,523.a & with CA/C1'; ~disp :s58; ~surf :s58; disp :flp; surf :flp; wait 10; turn x 1 40; wait; turn y -1 30; wait [END COMMANDS] [TEXT] The inhibitor flurbiprofen (blue) is nonselective because it fits well in the sites of both isoforms.
Click to view: COX-1 residues COX-2 residues both sets[END TEXT] [UNDO] ~disp #1:434.a,518.a,523.a; disp #0:434.a,518.a,523.a & with CA/C1'; ~disp :flp; ~surf :flp; disp :s58; surf :s58 [END UNDO] [END] [START] [UNDO] [END UNDO] [TEXT] Structures:
References:
Picot et al., Nature 367:243 (1994)
Kurumbail et al., Nature 384:644 (1996)
How to create your own demo [END TEXT] [END]