[INFO]
TITLE Cyclooxygenase Demo
AUTODELAY 5
[END INFO]

[START AUTODELAY=15]
[TEXT]
A common problem in drug design is attaining selectivity.  It may be
desirable for a drug to bind to a particular protein but not to
another protein that is very similar.  A well-known example involves
aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs. 
They inhibit the enzyme <i>cyclooxygenase</i> (COX), 
which has different isoforms.
<p>
Click <b>Next</b> 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 <b><font color="dark cyan">COX-1 isoform</font></b> (cyan)
contributes to many beneficial functions
(for example, protecting the lining of the stomach),
but the <font color="dark magenta"><b>COX-2 isoform</b></font> (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.
<p>
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 <font color="blue"><b>flurbiprofen</b></font>
(blue) is bound to COX-1, and the COX-2-selective inhibitor 
<font color="red"><b>SC-558</b></font> (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.
<p>
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.
<pre>
<font color="black"><b>Click to view the side chains as:</b></font>
<a cmd="repr stick :434.a,518.a,523.a; repr bs @ca">sticks</a>    <a cmd="repr sphere :434.a,518.a,523.a">spheres</a>
</pre>
[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).
<pre>
<font color="black"><b>Click to view:</b></font>
   <a cmd="~disp  #1:434.a,518.a,523.a; disp #0:434.a,518.a,523.a & with CA/C1'">COX-1 residues</a>     <a cmd="~disp #0:434.a,518.a,523.a; disp #1:434.a,518.a,523.a & with CA/C1'">COX-2 residues</a>     <a cmd="disp :434.a,518.a,523.a & with CA/C1'">both sets</a>
</pre>
[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.
<pre>
<font color="black"><b>Click to view:</b></font>
   <a cmd="~disp  #1:434.a,518.a,523.a; disp #0:434.a,518.a,523.a & with CA/C1'">COX-1 residues</a>     <a cmd="~disp #0:434.a,518.a,523.a; disp #1:434.a,518.a,523.a & with CA/C1'">COX-2 residues</a>     <a cmd="disp :434.a,518.a,523.a & with CA/C1'">both sets</a>
</pre>
[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]
<b>Structures</b>: 
<br>PDB files 1cqe (COX-1) and 6cox (COX-2)
<p>
<b>References</b>: 
<br>Picot et al., Nature 367:243 (1994)
<br>Kurumbail et al., Nature 384:644 (1996)
<p>
<a pycode="help.display('ContributedSoftware/demos/demos.html#demo')">
How to create your own demo</a>
[END TEXT]
[END]