Five atomic resolution structures of endothiapepsin inhibitor complexes: implications for the aspartic proteinase mechanism


Coates, L., Erskine, P.T., Crump, M.P., Wood, S.P. and Cooper, J.B. (2002) Five atomic resolution structures of endothiapepsin inhibitor complexes: implications for the aspartic proteinase mechanism. Journal of Molecular Biology, 318, (5), 1405-1415. (doi:10.1016/S0022-2836(02)00197-3).

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Description/Abstract

Endothiapepsin is derived from the fungus Endothia parasitica and is a
member of the aspartic proteinase class of enzymes. This class of enzyme
is comprised of two structurally similar lobes, each lobe contributing an
aspartic acid residue to form a catalytic dyad that acts to cleave the substrate
peptide bond. The three-dimensional structures of endothiapepsin
bound to five transition state analogue inhibitors (H189, H256, CP-80,794,
PD-129,541 and PD-130,328) have been solved at atomic resolution allowing
full anisotropic modelling of each complex. The active sites of the
five structures have been studied with a view to studying the catalytic
mechanism of the aspartic proteinases by locating the active site protons
by carboxyl bond length differences and electron density analysis. In the
CP-80,794 structure there is excellent electron density for the hydrogen
on the inhibitory statine hydroxyl group which forms a hydrogen bond
with the inner oxygen of Asp32. The location of this proton has implications
for the catalytic mechanism of the aspartic proteinases as it is consistent
with the proposed mechanism in which Asp32 is the negatively
charged aspartate. A number of short hydrogen bonds (,2.6A ° ) with
ESD values of around 0.01 A ° that may have a role in catalysis have been
identified within the active site of each structure; the lengths of these
bonds have been confirmed using NMR techniques. The possibility and
implications of low barrier hydrogen bonds in the active site are
considered.

Item Type: Article
ISSNs: 0022-2836 (print)
Related URLs:
Keywords: anisotropic refinement, aspartic proteinase mechanism, atomic resolution, tetrahedral intermediate, transition-state analogues
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: University Structure - Pre August 2011 > School of Biological Sciences
ePrint ID: 24102
Date Deposited: 22 Mar 2006
Last Modified: 27 Mar 2014 18:13
Contact Email Address: J.B.Cooper@soton.ac.uk
URI: http://eprints.soton.ac.uk/id/eprint/24102

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