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3th7

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Revision as of 15:53, 20 November 2019

Crystal structure of unliganded Co2+2-HAI (pH 7.0)

Structural highlights

3th7 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	3tf3, 2pha, 3the, 3thh, 3thj, 2aeb
Gene:	ARG1 (HUMAN)
Activity:	Arginase, with EC number 3.5.3.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[ARGI1_HUMAN] Defects in ARG1 are the cause of argininemia (ARGIN) [MIM:207800]; also known as hyperargininemia. Argininemia is a rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia, progressive spastic quadriplegia.^[1] ^[2]

Publication Abstract from PubMed

The binuclear manganese metalloenzyme human arginase I (HAI) is a potential protein drug for cancer chemotherapy, in that it is capable of depleting extracellular l-Arg levels in the microenvironment of tumor cells that require this nutrient to thrive. Substitution of the native Mn(2+)(2) cluster with a Co(2+)(2) cluster in the active site yields an enzyme with enhanced catalytic activity at physiological pH ( approximately 7.4) that could serve as an improved protein drug for l-Arg depletion therapy [Stone, E. M., Glazer, E. S., Chantranupong, L., Cherukuri, P., Breece, R. M., Tierney, D. L., Curley, S. A., Iverson, B. L., and Georgiou, G. (2010) ACS Chem. Biol. 5, 333-342]. A different catalytic mechanism is proposed for Co(2+)(2)-HAI compared with that of Mn(2+)(2)-HAI, including an unusual Nepsilon-Co(2+) coordination mode, to rationalize the lower K(M) value of l-Arg and the lower K(i) value of l-Orn. However, we now report that no unusual metal coordination modes are observed in the cobalt-reconstituted enzyme. The X-ray crystal structures of unliganded Co(2+)(2)-HAI determined at 2.10 A resolution (pH 7.0) and 1.97 A resolution (pH 8.5), as well as the structures of Co(2+)(2)-HAI complexed with the reactive substrate analogue 2(S)-amino-6-boronohexanoic acid (ABH, pH 7.0) and the catalytic product l-Orn (pH 7.0) determined at 1.85 and 1.50 A resolution, respectively, are essentially identical to the corresponding structures of Mn(2+)(2)-HAI. Therefore, in the absence of significant structural differences between Co(2+)(2)-HAI and Mn(2+)(2)-HAI, we suggest that a higher concentration of metal-bridging hydroxide ion at physiological pH for Co(2+)(2)-HAI, a consequence of the lower pK(a) of a Co(2+)-bound water molecule compared with a Mn(2+)-bound water molecule, strengthens electrostatic interactions with cationic amino acids and accounts for enhanced affinity as reflected in the lower K(M) value of l-Arg and the lower K(i) value of l-Orn.

Crystal structures of complexes with cobalt-reconstituted human arginase I.,D'Antonio EL, Christianson DW Biochemistry. 2011 Sep 20;50(37):8018-27. Epub 2011 Aug 26. PMID:21870783^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Uchino T, Haraguchi Y, Aparicio JM, Mizutani N, Higashikawa M, Naitoh H, Mori M, Matsuda I. Three novel mutations in the liver-type arginase gene in three unrelated Japanese patients with argininemia. Am J Hum Genet. 1992 Dec;51(6):1406-12. PMID:1463019
↑ Uchino T, Snyderman SE, Lambert M, Qureshi IA, Shapira SK, Sansaricq C, Smit LM, Jakobs C, Matsuda I. Molecular basis of phenotypic variation in patients with argininemia. Hum Genet. 1995 Sep;96(3):255-60. PMID:7649538
↑ D'Antonio EL, Christianson DW. Crystal structures of complexes with cobalt-reconstituted human arginase I. Biochemistry. 2011 Sep 20;50(37):8018-27. Epub 2011 Aug 26. PMID:21870783 doi:10.1021/bi201101t

1 Structural highlights
2 Disease
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3th7"

@@ Line 1: / Line 1: @@
 ==Crystal structure of unliganded Co2+2-HAI (pH 7.0)==
-<StructureSection load='3th7' size='340' side='right' caption='[[3th7]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+<StructureSection load='3th7' size='340' side='right'caption='[[3th7]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[3th7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TH7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TH7 FirstGlance]. <br>
@@ Line 23: / Line 23: @@
 ==See Also==
-*[[Arginase|Arginase]]
+*[[Arginase 3D structures|Arginase 3D structures]]
 == References ==
 <references/>
@@ Line 30: / Line 30: @@
 [[Category: Arginase]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Antonio, E L.D]]
 [[Category: Christianson, D W]]
 [[Category: Arginase fold]]
 [[Category: Hydrolase]]

3th7

From Proteopedia

Revision as of 15:53, 20 November 2019

Crystal structure of unliganded Co2+2-HAI (pH 7.0)

Structural highlights

Disease

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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