1z7x: Difference between revisions

Revision as of 11:36, 23 January 2008

X-ray structure of human ribonuclease inhibitor complexed with ribonuclease I

OverviewOverview

The ribonuclease inhibitor protein (RI) binds to members of the bovine, pancreatic ribonuclease (RNase A) superfamily with an affinity in the, femtomolar range. Here, we report on structural and energetic aspects of, the interaction between human RI (hRI) and human pancreatic ribonuclease, (RNase 1). The structure of the crystalline hRI x RNase 1 complex was, determined at a resolution of 1.95 A, revealing the formation of 19, intermolecular hydrogen bonds involving 13 residues of RNase 1. In, contrast, only nine such hydrogen bonds are apparent in the structure of, the complex between porcine RI and RNase A. hRI, which is anionic, also, appears to use its horseshoe-shaped structure to engender long-range, Coulombic interactions with RNase 1, which is cationic. In accordance with, the structural data, the hRI.RNase 1 complex was found to be extremely, stable (t(1/2)=81 days; K(d)=2.9 x 10(-16) M). Site-directed mutagenesis, experiments enabled the identification of two cationic residues in RNase, 1, Arg39 and Arg91, that are especially important for both the formation, and stability of the complex, and are thus termed "electrostatic targeting, residues". Disturbing the electrostatic attraction between hRI and RNase 1, yielded a variant of RNase 1 that maintained ribonucleolytic activity and, conformational stability but had a 2.8 x 10(3)-fold lower association rate, for complex formation and 5.9 x 10(9)-fold lower affinity for hRI. This, variant of RNase 1, which exhibits the largest decrease in RI affinity of, any engineered ribonuclease, is also toxic to human erythroleukemia cells., Together, these results provide new insight into an unusual and important, protein-protein interaction, and could expedite the development of human, ribonucleases as chemotherapeutic agents.

About this StructureAbout this Structure

1Z7X is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Pancreatic ribonuclease, with EC number 3.1.27.5 Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

Inhibition of human pancreatic ribonuclease by the human ribonuclease inhibitor protein., Johnson RJ, McCoy JG, Bingman CA, Phillips GN Jr, Raines RT, J Mol Biol. 2007 Apr 27;368(2):434-49. Epub 2007 Feb 9. PMID:17350650

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OCA

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-[[Image:1z7x.gif|left|200px]]<br />
+[[Image:1z7x.gif|left|200px]]<br /><applet load="1z7x" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1z7x" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1z7x, resolution 1.95&Aring;" />
 '''X-ray structure of human ribonuclease inhibitor complexed with ribonuclease I'''<br />
-==Disease==
+==Overview==
-Known diseases associated with this structure: Creutzfeldt-Jakob disease OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176640 176640]], Gerstmann-Straussler disease OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176640 176640]], Huntington disease-like 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176640 176640]], Insomnia, fatal familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176640 176640]], Prion disease with protracted course OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176640 176640]]
+The ribonuclease inhibitor protein (RI) binds to members of the bovine, pancreatic ribonuclease (RNase A) superfamily with an affinity in the, femtomolar range. Here, we report on structural and energetic aspects of, the interaction between human RI (hRI) and human pancreatic ribonuclease, (RNase 1). The structure of the crystalline hRI x RNase 1 complex was, determined at a resolution of 1.95 A, revealing the formation of 19, intermolecular hydrogen bonds involving 13 residues of RNase 1. In, contrast, only nine such hydrogen bonds are apparent in the structure of, the complex between porcine RI and RNase A. hRI, which is anionic, also, appears to use its horseshoe-shaped structure to engender long-range, Coulombic interactions with RNase 1, which is cationic. In accordance with, the structural data, the hRI.RNase 1 complex was found to be extremely, stable (t(1/2)=81 days; K(d)=2.9 x 10(-16) M). Site-directed mutagenesis, experiments enabled the identification of two cationic residues in RNase, 1, Arg39 and Arg91, that are especially important for both the formation, and stability of the complex, and are thus termed "electrostatic targeting, residues". Disturbing the electrostatic attraction between hRI and RNase 1, yielded a variant of RNase 1 that maintained ribonucleolytic activity and, conformational stability but had a 2.8 x 10(3)-fold lower association rate, for complex formation and 5.9 x 10(9)-fold lower affinity for hRI. This, variant of RNase 1, which exhibits the largest decrease in RI affinity of, any engineered ribonuclease, is also toxic to human erythroleukemia cells., Together, these results provide new insight into an unusual and important, protein-protein interaction, and could expedite the development of human, ribonucleases as chemotherapeutic agents.
 ==About this Structure==
-Z7X is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CIT as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Pancreatic_ribonuclease Pancreatic ribonuclease], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.27.5 3.1.27.5] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1Z7X OCA].
+Z7X is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CIT:'>CIT</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Pancreatic_ribonuclease Pancreatic ribonuclease], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.27.5 3.1.27.5] Known structural/functional Site: <scene name='pdbsite=AC1:Cit Binding Site For Residue X 900'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Z7X OCA].
+==Reference==
+Inhibition of human pancreatic ribonuclease by the human ribonuclease inhibitor protein., Johnson RJ, McCoy JG, Bingman CA, Phillips GN Jr, Raines RT, J Mol Biol. 2007 Apr 27;368(2):434-49. Epub 2007 Feb 9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17350650 17350650]
 [[Category: Homo sapiens]]
 [[Category: Pancreatic ribonuclease]]
@@ Line 23: / Line 25: @@
 [[Category: cesg]]
 [[Category: enzyme-inhibitor complex]]
+[[Category: hydrolase/hydrolase inhibitor complex]]
 [[Category: leucine-rich repeat]]
 [[Category: protein structure initiative]]
@@ Line 29: / Line 32: @@
 [[Category: structural genomics]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:30:40 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 10:36:14 2008''