1q83: Difference between revisions

Revision as of 15:36, 21 February 2008

Crystal structure of the mouse acetylcholinesterase-TZ2PA6 syn complex

OverviewOverview

The 1,3-dipolar cycloaddition reaction between unactivated azides and acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs inside the active center gorge of acetylcholinesterase (AChE) between certain azide and acetylene reactants, attached via methylene chains to specific inhibitor moieties selective for the active center and peripheral site of the enzyme. AChE catalyzes the formation of its own inhibitor in a highly selective fashion: only a single syn1-triazole regioisomer with defined substitution positions and linker distances is generated from a series of reagent combinations. Inhibition measurements revealed this syn1-triazole isomer to be the highest affinity reversible organic inhibitor of AChE with association rate constants near the diffusion limit. The corresponding anti1 isomer, not formed by the enzyme, proved to be a respectable but weaker inhibitor. The crystal structures of the syn1- and anti1-mouse AChE complexes at 2.45- to 2.65-A resolution reveal not only substantial binding contributions from the triazole moieties, but also that binding of the syn1 isomer induces large and unprecedented enzyme conformational changes not observed in the anti1 complex nor predicted from structures of the apoenzyme and complexes with the precursor reactants. Hence, the freeze-frame reaction offers both a strategically original approach for drug discovery and a means for kinetically controlled capture, as a high-affinity complex between the enzyme and its self-created inhibitor, of a highly reactive minor abundance conformer of a fluctuating protein template.

About this StructureAbout this Structure

1Q83 is a Single protein structure of sequence from Mus musculus with , and as ligands. Active as Acetylcholinesterase, with EC number 3.1.1.7 Full crystallographic information is available from OCA.

ReferenceReference

Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation., Bourne Y, Kolb HC, Radic Z, Sharpless KB, Taylor P, Marchot P, Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1449-54. Epub 2004 Feb 2. PMID:14757816

Page seeded by OCA on Thu Feb 21 14:36:50 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:1q83.gif|left|200px]]<br /><applet load="1q83" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1q83.gif|left|200px]]<br /><applet load="1q83" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1q83, resolution 2.65&Aring;" />
 '''Crystal structure of the mouse acetylcholinesterase-TZ2PA6 syn complex'''<br />
 ==Overview==
-The 1,3-dipolar cycloaddition reaction between unactivated azides and, acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs, inside the active center gorge of acetylcholinesterase (AChE) between, certain azide and acetylene reactants, attached via methylene chains to, specific inhibitor moieties selective for the active center and peripheral, site of the enzyme. AChE catalyzes the formation of its own inhibitor in a, highly selective fashion: only a single syn1-triazole regioisomer with, defined substitution positions and linker distances is generated from a, series of reagent combinations. Inhibition measurements revealed this, syn1-triazole isomer to be the highest affinity reversible organic, inhibitor of AChE with association rate constants near the diffusion, limit. The corresponding anti1 isomer, not formed by the enzyme, proved to, be a respectable but weaker inhibitor. The crystal structures of the syn1-, and anti1-mouse AChE complexes at 2.45- to 2.65-A resolution reveal not, only substantial binding contributions from the triazole moieties, but, also that binding of the syn1 isomer induces large and unprecedented, enzyme conformational changes not observed in the anti1 complex nor, predicted from structures of the apoenzyme and complexes with the, precursor reactants. Hence, the freeze-frame reaction offers both a, strategically original approach for drug discovery and a means for, kinetically controlled capture, as a high-affinity complex between the, enzyme and its self-created inhibitor, of a highly reactive minor, abundance conformer of a fluctuating protein template.
+The 1,3-dipolar cycloaddition reaction between unactivated azides and acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs inside the active center gorge of acetylcholinesterase (AChE) between certain azide and acetylene reactants, attached via methylene chains to specific inhibitor moieties selective for the active center and peripheral site of the enzyme. AChE catalyzes the formation of its own inhibitor in a highly selective fashion: only a single syn1-triazole regioisomer with defined substitution positions and linker distances is generated from a series of reagent combinations. Inhibition measurements revealed this syn1-triazole isomer to be the highest affinity reversible organic inhibitor of AChE with association rate constants near the diffusion limit. The corresponding anti1 isomer, not formed by the enzyme, proved to be a respectable but weaker inhibitor. The crystal structures of the syn1- and anti1-mouse AChE complexes at 2.45- to 2.65-A resolution reveal not only substantial binding contributions from the triazole moieties, but also that binding of the syn1 isomer induces large and unprecedented enzyme conformational changes not observed in the anti1 complex nor predicted from structures of the apoenzyme and complexes with the precursor reactants. Hence, the freeze-frame reaction offers both a strategically original approach for drug discovery and a means for kinetically controlled capture, as a high-affinity complex between the enzyme and its self-created inhibitor, of a highly reactive minor abundance conformer of a fluctuating protein template.
 ==About this Structure==
-Q83 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with NAG, P6G and TZ5 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.7 3.1.1.7] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1Q83 OCA].
+Q83 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=NAG:'>NAG</scene>, <scene name='pdbligand=P6G:'>P6G</scene> and <scene name='pdbligand=TZ5:'>TZ5</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.7 3.1.1.7] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Q83 OCA].
 ==Reference==
@@ Line 15: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Bourne, Y.]]
-[[Category: Kolb, H.C.]]
+[[Category: Kolb, H C.]]
 [[Category: Marchot, P.]]
 [[Category: Radic, Z.]]
-[[Category: Sharpless, K.B.]]
+[[Category: Sharpless, K B.]]
 [[Category: Taylor, P.]]
 [[Category: NAG]]
@@ Line 28: / Line 28: @@
 [[Category: serine esterase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 00:28:27 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:36:50 2008''