1xn3: Difference between revisions

Revision as of 16:56, 21 February 2008

Crystal structure of Beta-secretase bound to a long inhibitor with additional upstream residues.

OverviewOverview

Memapsin 2 (beta-secretase) is the membrane-anchored aspartic protease that initiates the cleavage of beta-amyloid precursor protein (APP), leading to the production of amyloid-beta (Abeta), a major factor in the pathogenesis of Alzheimer's disease. The active site of memapsin 2 has been shown, with kinetic data and crystal structures, to bind to eight substrate residues (P(4)-P(4)'). We describe here that the addition of three substrate residues from P(7) to P(5) strongly influences the hydrolytic activity by memapsin 2 and these subsites prefer hydrophobic residues, especially tryptophan. A crystal structure of memapsin 2 complexed with a statine-based inhibitor spanning P(10)-P(4)' revealed the binding positions of P(5)-P(7) residues. Kinetic studies revealed that the addition of these substrate residues contributes to the decrease in K(m) and increase in k(cat) values, suggesting that these residues contribute to both substrate recognition and transition-state binding. The crystal structure of a new inhibitor, OM03-4 (K(i) = 0.03 nM), bound to memapsin 2 revealed the interaction of a tryptophan with the S(6) subsite of the protease.

About this StructureAbout this Structure

1XN3 is a Single protein structure of sequence from Homo sapiens. Active as Memapsin 2, with EC number 3.4.23.46 Full crystallographic information is available from OCA.

ReferenceReference

Structural locations and functional roles of new subsites S5, S6, and S7 in memapsin 2 (beta-secretase)., Turner RT 3rd, Hong L, Koelsch G, Ghosh AK, Tang J, Biochemistry. 2005 Jan 11;44(1):105-12. PMID:15628850

Page seeded by OCA on Thu Feb 21 15:56:38 2008

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OCA

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-[[Image:1xn3.gif|left|200px]]<br />
+[[Image:1xn3.gif|left|200px]]<br /><applet load="1xn3" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1xn3" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1xn3, resolution 2.0&Aring;" />
 '''Crystal structure of Beta-secretase bound to a long inhibitor with additional upstream residues.'''<br />
 ==Overview==
-Memapsin 2 (beta-secretase) is the membrane-anchored aspartic protease, that initiates the cleavage of beta-amyloid precursor protein (APP), leading to the production of amyloid-beta (Abeta), a major factor in the, pathogenesis of Alzheimer's disease. The active site of memapsin 2 has, been shown, with kinetic data and crystal structures, to bind to eight, substrate residues (P(4)-P(4)'). We describe here that the addition of, three substrate residues from P(7) to P(5) strongly influences the, hydrolytic activity by memapsin 2 and these subsites prefer hydrophobic, residues, especially tryptophan. A crystal structure of memapsin 2, complexed with a statine-based inhibitor spanning P(10)-P(4)' revealed the, binding positions of P(5)-P(7) residues. Kinetic studies revealed that the, addition of these substrate residues contributes to the decrease in K(m), and increase in k(cat) values, suggesting that these residues contribute, to both substrate recognition and transition-state binding. The crystal, structure of a new inhibitor, OM03-4 (K(i) = 0.03 nM), bound to memapsin 2, revealed the interaction of a tryptophan with the S(6) subsite of the, protease.
+Memapsin 2 (beta-secretase) is the membrane-anchored aspartic protease that initiates the cleavage of beta-amyloid precursor protein (APP), leading to the production of amyloid-beta (Abeta), a major factor in the pathogenesis of Alzheimer's disease. The active site of memapsin 2 has been shown, with kinetic data and crystal structures, to bind to eight substrate residues (P(4)-P(4)'). We describe here that the addition of three substrate residues from P(7) to P(5) strongly influences the hydrolytic activity by memapsin 2 and these subsites prefer hydrophobic residues, especially tryptophan. A crystal structure of memapsin 2 complexed with a statine-based inhibitor spanning P(10)-P(4)' revealed the binding positions of P(5)-P(7) residues. Kinetic studies revealed that the addition of these substrate residues contributes to the decrease in K(m) and increase in k(cat) values, suggesting that these residues contribute to both substrate recognition and transition-state binding. The crystal structure of a new inhibitor, OM03-4 (K(i) = 0.03 nM), bound to memapsin 2 revealed the interaction of a tryptophan with the S(6) subsite of the protease.
 ==About this Structure==
-XN3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1XN3 OCA].
+XN3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XN3 OCA].
 ==Reference==
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 [[Category: Memapsin 2]]
 [[Category: Single protein]]
-[[Category: Ghosh, A.K.]]
+[[Category: Ghosh, A K.]]
 [[Category: Hong, L.]]
-[[Category: III, R.T.Turner.]]
+[[Category: III, R T.Turner.]]
 [[Category: Koelsch, G.]]
 [[Category: Tang, J.]]
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 [[Category: memapsin2]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:08:12 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:56:38 2008''