4er4: Difference between revisions

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HIGH-RESOLUTION X-RAY ANALYSES OF RENIN INHIBITOR-ASPARTIC PROTEINASE COMPLEXES

OverviewOverview

Inhibitors of the conversion of angiotensinogen to the vasoconstrictor angiotensin II have considerable value as antihypertensive agents. For example, captopril and enalapril are clinically useful as inhibitors of angiotensin-converting enzyme. This has encouraged intense activity in the development of inhibitors of kidney renin, which is a very specific aspartic proteinase catalysing the first and rate limiting step in the conversion of angiotensinogen to angiotensin II. The most effective inhibitors such as H-142 and L-363,564 have used non-hydrolysable analogues of the proposed transition state, and partial sequences of angiotensinogen (Table 1). H-142 is effective in lowering blood pressure in humans but has no significant effect on other aspartic proteinases such as pepsin in the human body (Table 1). At present there are no crystal structures available for human or mouse renins although three-dimensional models demonstrate close structural similarity to other spartic proteinases. We have therefore determined by X-ray analysis the three-dimensional structures of H-142 and L-363,564 complexed with the aspartic proteinase endothiapepsin, which binds these inhibitors with affinities not greatly different from those measured against human renin (Table 1). The structures of these complexes and of that between endothiapepsin and the general aspartic proteinase inhibitor, H-256 (Table 1) define the common hydrogen bonding schemes that allow subtle differences in side-chain orientations and in the positions of the transition state analogues with respect to the active-site aspartates.

About this StructureAbout this Structure

4ER4 is a Single protein structure of sequence from Cryphonectria parasitica. Active as Hydrolase, with EC number 3.4.23.18, 3.4.23.28 and 3.4.23.30 3.4.21.103, 3.4.23.18, 3.4.23.28 and 3.4.23.30 Full crystallographic information is available from OCA.

ReferenceReference

High resolution X-ray analyses of renin inhibitor-aspartic proteinase complexes., Foundling SI, Cooper J, Watson FE, Cleasby A, Pearl LH, Sibanda BL, Hemmings A, Wood SP, Blundell TL, Valler MJ, et al., Nature. 1987 May 28-Jun 3;327(6120):349-52. PMID:3295561

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-[[Image:4er4.jpg|left|200px]]<br /><applet load="4er4" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:4er4.jpg|left|200px]]<br /><applet load="4er4" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="4er4, resolution 2.1&Aring;" />
 '''HIGH-RESOLUTION X-RAY ANALYSES OF RENIN INHIBITOR-ASPARTIC PROTEINASE COMPLEXES'''<br />
 ==Overview==
-Inhibitors of the conversion of angiotensinogen to the vasoconstrictor, angiotensin II have considerable value as antihypertensive agents. For, example, captopril and enalapril are clinically useful as inhibitors of, angiotensin-converting enzyme. This has encouraged intense activity in the, development of inhibitors of kidney renin, which is a very specific, aspartic proteinase catalysing the first and rate limiting step in the, conversion of angiotensinogen to angiotensin II. The most effective, inhibitors such as H-142 and L-363,564 have used non-hydrolysable, analogues of the proposed transition state, and partial sequences of, angiotensinogen (Table 1). H-142 is effective in lowering blood pressure, in humans but has no significant effect on other aspartic proteinases such, as pepsin in the human body (Table 1). At present there are no crystal, structures available for human or mouse renins although three-dimensional, models demonstrate close structural similarity to other spartic, proteinases. We have therefore determined by X-ray analysis the, three-dimensional structures of H-142 and L-363,564 complexed with the, aspartic proteinase endothiapepsin, which binds these inhibitors with, affinities not greatly different from those measured against human renin, (Table 1). The structures of these complexes and of that between, endothiapepsin and the general aspartic proteinase inhibitor, H-256 (Table, 1) define the common hydrogen bonding schemes that allow subtle, differences in side-chain orientations and in the positions of the, transition state analogues with respect to the active-site aspartates.
+Inhibitors of the conversion of angiotensinogen to the vasoconstrictor angiotensin II have considerable value as antihypertensive agents. For example, captopril and enalapril are clinically useful as inhibitors of angiotensin-converting enzyme. This has encouraged intense activity in the development of inhibitors of kidney renin, which is a very specific aspartic proteinase catalysing the first and rate limiting step in the conversion of angiotensinogen to angiotensin II. The most effective inhibitors such as H-142 and L-363,564 have used non-hydrolysable analogues of the proposed transition state, and partial sequences of angiotensinogen (Table 1). H-142 is effective in lowering blood pressure in humans but has no significant effect on other aspartic proteinases such as pepsin in the human body (Table 1). At present there are no crystal structures available for human or mouse renins although three-dimensional models demonstrate close structural similarity to other spartic proteinases. We have therefore determined by X-ray analysis the three-dimensional structures of H-142 and L-363,564 complexed with the aspartic proteinase endothiapepsin, which binds these inhibitors with affinities not greatly different from those measured against human renin (Table 1). The structures of these complexes and of that between endothiapepsin and the general aspartic proteinase inhibitor, H-256 (Table 1) define the common hydrogen bonding schemes that allow subtle differences in side-chain orientations and in the positions of the transition state analogues with respect to the active-site aspartates.
 ==About this Structure==
-ER4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Cryphonectria_parasitica Cryphonectria parasitica]. Active as [http://en.wikipedia.org/wiki/Hydrolase Hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.103, 3.4.23.18, 3.4.23.28 and 3.4.23.30 3.4.21.103, 3.4.23.18, 3.4.23.28 and 3.4.23.30] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=4ER4 OCA].
+ER4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Cryphonectria_parasitica Cryphonectria parasitica]. Active as [http://en.wikipedia.org/wiki/Hydrolase Hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.103, 3.4.23.18, 3.4.23.28 and 3.4.23.30 3.4.21.103, 3.4.23.18, 3.4.23.28 and 3.4.23.30] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ER4 OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Hydrolase]]
 [[Category: Single protein]]
-[[Category: Blundell, T.L.]]
+[[Category: Blundell, T L.]]
-[[Category: Foundling, S.I.]]
+[[Category: Foundling, S I.]]
 [[Category: Szelke, M.]]
-[[Category: Watson, F.E.]]
+[[Category: Watson, F E.]]
 [[Category: hydrolase (acid proteinase)]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 19:34:02 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:13:12 2008''