2aeb: Difference between revisions

Revision as of 17:26, 21 February 2008

Crystal structure of human arginase I at 1.29 A resolution and exploration of inhibition in immune response.

OverviewOverview

Human arginase I is a potential target for therapeutic intervention in diseases linked to compromised l-arginine homeostasis. Here, we report high-affinity binding of the reaction coordinate analogue inhibitors 2(S)-amino-6-boronohexanoic acid (ABH, Kd = 5 nM) and S-(2-boronoethyl)-l-cysteine (BEC, Kd = 270 nM) to human arginase I, and we report x-ray crystal structures of the respective enzyme-inhibitor complexes at 1.29- and 1.94-A resolution determined from crystals twinned by hemihedry. The ultrahigh-resolution structure of the human arginase I-ABH complex yields an unprecedented view of the binuclear manganese cluster and illuminates the structural basis for nanomolar affinity: bidentate inner-sphere boronate-manganese coordination interactions and fully saturated hydrogen bond networks with inhibitor alpha-amino and alpha-carboxylate groups. These interactions are therefore implicated in the stabilization of the transition state for l-arginine hydrolysis. Electron density maps also reveal that active-site residue H141 is protonated as the imidazolium cation. The location of H141 is such that it could function as a general acid to protonate the leaving amino group of l-ornithine during catalysis, and this is a revised mechanistic proposal for arginase. This work serves as a foundation for studying the structural and chemical biology of arginase I in the immune response, and we demonstrate the inhibition of arginase activity by ABH in human and murine myeloid cells.

About this StructureAbout this Structure

2AEB is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Arginase, with EC number 3.5.3.1 Full crystallographic information is available from OCA.

ReferenceReference

Crystal structure of human arginase I at 1.29-A resolution and exploration of inhibition in the immune response., Di Costanzo L, Sabio G, Mora A, Rodriguez PC, Ochoa AC, Centeno F, Christianson DW, Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13058-63. Epub 2005 Sep 2. PMID:16141327

Page seeded by OCA on Thu Feb 21 16:26:29 2008

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

OCA

@@ Line 1: / Line 1: @@
-[[Image:2aeb.gif|left|200px]]<br />
+[[Image:2aeb.gif|left|200px]]<br /><applet load="2aeb" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2aeb" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2aeb, resolution 1.29&Aring;" />
 '''Crystal structure of human arginase I at 1.29 A resolution and exploration of inhibition in immune response.'''<br />
 ==Overview==
-Human arginase I is a potential target for therapeutic intervention in, diseases linked to compromised l-arginine homeostasis. Here, we report, high-affinity binding of the reaction coordinate analogue inhibitors, 2(S)-amino-6-boronohexanoic acid (ABH, Kd = 5 nM) and, S-(2-boronoethyl)-l-cysteine (BEC, Kd = 270 nM) to human arginase I, and, we report x-ray crystal structures of the respective enzyme-inhibitor, complexes at 1.29- and 1.94-A resolution determined from crystals twinned, by hemihedry. The ultrahigh-resolution structure of the human arginase, I-ABH complex yields an unprecedented view of the binuclear manganese, cluster and illuminates the structural basis for nanomolar affinity:, bidentate inner-sphere boronate-manganese coordination interactions and, fully saturated hydrogen bond networks with inhibitor alpha-amino and, alpha-carboxylate groups. These interactions are therefore implicated in, the stabilization of the transition state for l-arginine hydrolysis., Electron density maps also reveal that active-site residue H141 is, protonated as the imidazolium cation. The location of H141 is such that it, could function as a general acid to protonate the leaving amino group of, l-ornithine during catalysis, and this is a revised mechanistic proposal, for arginase. This work serves as a foundation for studying the structural, and chemical biology of arginase I in the immune response, and we, demonstrate the inhibition of arginase activity by ABH in human and murine, myeloid cells.
+Human arginase I is a potential target for therapeutic intervention in diseases linked to compromised l-arginine homeostasis. Here, we report high-affinity binding of the reaction coordinate analogue inhibitors 2(S)-amino-6-boronohexanoic acid (ABH, Kd = 5 nM) and S-(2-boronoethyl)-l-cysteine (BEC, Kd = 270 nM) to human arginase I, and we report x-ray crystal structures of the respective enzyme-inhibitor complexes at 1.29- and 1.94-A resolution determined from crystals twinned by hemihedry. The ultrahigh-resolution structure of the human arginase I-ABH complex yields an unprecedented view of the binuclear manganese cluster and illuminates the structural basis for nanomolar affinity: bidentate inner-sphere boronate-manganese coordination interactions and fully saturated hydrogen bond networks with inhibitor alpha-amino and alpha-carboxylate groups. These interactions are therefore implicated in the stabilization of the transition state for l-arginine hydrolysis. Electron density maps also reveal that active-site residue H141 is protonated as the imidazolium cation. The location of H141 is such that it could function as a general acid to protonate the leaving amino group of l-ornithine during catalysis, and this is a revised mechanistic proposal for arginase. This work serves as a foundation for studying the structural and chemical biology of arginase I in the immune response, and we demonstrate the inhibition of arginase activity by ABH in human and murine myeloid cells.
 ==About this Structure==
-AEB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MN and AB5 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Arginase Arginase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.3.1 3.5.3.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2AEB OCA].
+AEB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MN:'>MN</scene> and <scene name='pdbligand=AB5:'>AB5</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Arginase Arginase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.3.1 3.5.3.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AEB OCA].
 ==Reference==
@@ Line 16: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Centeno, F.]]
-[[Category: Christianson, D.W.]]
+[[Category: Christianson, D W.]]
-[[Category: Costanzo, L.Di.]]
+[[Category: Costanzo, L Di.]]
 [[Category: Mora, A.]]
-[[Category: Ochoa, A.C.]]
+[[Category: Ochoa, A C.]]
-[[Category: Rodriguez, P.C.]]
+[[Category: Rodriguez, P C.]]
 [[Category: Sabio, G.]]
 [[Category: AB5]]
@@ Line 29: / Line 28: @@
 [[Category: perfectly twinned crystal]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:49:44 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:26:29 2008''