2r9p: Difference between revisions

Revision as of 16:29, 4 May 2008

Human mesotrypsin complexed with bovine pancreatic trypsin inhibitor(BPTI)

OverviewOverview

Human mesotrypsin is an isoform of trypsin that displays unusual resistance to polypeptide trypsin inhibitors and has been observed to cleave several such inhibitors as substrates. Whereas substitution of arginine for the highly conserved glycine 193 in the trypsin active site has been implicated as a critical factor in the inhibitor resistance of mesotrypsin, how this substitution leads to accelerated inhibitor cleavage is not clear. Bovine pancreatic trypsin inhibitor (BPTI) forms an extremely stable and cleavage-resistant complex with trypsin, and thus provides a rigorous challenge of mesotrypsin catalytic activity toward polypeptide inhibitors. Here, we report kinetic constants for mesotrypsin and the highly homologous (but inhibitor sensitive) human cationic trypsin, describing inhibition by, and cleavage of BPTI, as well as crystal structures of the mesotrypsin-BPTI and human cationic trypsin-BPTI complexes. We find that mesotrypsin cleaves BPTI with a rate constant accelerated 350-fold over that of human cationic trypsin and 150,000-fold over that of bovine trypsin. From the crystal structures, we see that small conformational adjustments limited to several side chains enable mesotrypsin-BPTI complex formation, surmounting the predicted steric clash introduced by Arg-193. Our results show that the mesotrypsin-BPTI interface favors catalysis through (a) electrostatic repulsion between the closely spaced mesotrypsin Arg-193 and BPTI Arg-17, and (b) elimination of two hydrogen bonds between the enzyme and the amine leaving group portion of BPTI. Our model predicts that these deleterious interactions accelerate leaving group dissociation and deacylation.

About this StructureAbout this Structure

2R9P is a Protein complex structure of sequences from Bos taurus and Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Structural Basis for Accelerated Cleavage of Bovine Pancreatic Trypsin Inhibitor (BPTI) by Human Mesotrypsin., Salameh MA, Soares AS, Hockla A, Radisky ES, J Biol Chem. 2008 Feb 15;283(7):4115-23. Epub 2007 Dec 12. PMID:18077447 Page seeded by OCA on Sun May 4 16:29:09 2008

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

OCA

@@ Line 1: / Line 1: @@
 [[Image:2r9p.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2r9p |SIZE=350|CAPTION= <scene name='initialview01'>2r9p</scene>, resolution 1.4&Aring;
+The line below this paragraph, containing "STRUCTURE_2r9p", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Residue+C+1'>AC1</scene>, <scene name='pdbsite=AC2:So4+Binding+Site+For+Residue+E+59'>AC2</scene>, <scene name='pdbsite=AC3:So4+Binding+Site+For+Residue+F+59'>AC3</scene>, <scene name='pdbsite=AC4:So4+Binding+Site+For+Residue+F+60'>AC4</scene>, <scene name='pdbsite=AC5:So4+Binding+Site+For+Residue+G+59'>AC5</scene>, <scene name='pdbsite=AC6:So4+Binding+Site+For+Residue+B+6'>AC6</scene>, <scene name='pdbsite=AC7:So4+Binding+Site+For+Residue+A+7'>AC7</scene>, <scene name='pdbsite=AC8:So4+Binding+Site+For+Residue+D+8'>AC8</scene>, <scene name='pdbsite=AC9:So4+Binding+Site+For+Residue+G+60'>AC9</scene>, <scene name='pdbsite=BC1:So4+Binding+Site+For+Residue+I+59'>BC1</scene>, <scene name='pdbsite=BC2:So4+Binding+Site+For+Residue+E+60'>BC2</scene>, <scene name='pdbsite=BC3:So4+Binding+Site+For+Residue+F+61'>BC3</scene>, <scene name='pdbsite=BC4:So4+Binding+Site+For+Residue+B+13'>BC4</scene>, <scene name='pdbsite=BC5:So4+Binding+Site+For+Residue+B+14'>BC5</scene>, <scene name='pdbsite=BC6:So4+Binding+Site+For+Residue+D+15'>BC6</scene>, <scene name='pdbsite=BC7:So4+Binding+Site+For+Residue+D+247'>BC7</scene>, <scene name='pdbsite=BC8:So4+Binding+Site+For+Residue+G+61'>BC8</scene>, <scene name='pdbsite=BC9:So4+Binding+Site+For+Residue+B+247'>BC9</scene>, <scene name='pdbsite=CC1:So4+Binding+Site+For+Residue+D+248'>CC1</scene> and <scene name='pdbsite=CC2:So4+Binding+Site+For+Residue+C+247'>CC2</scene>
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= PRSS3, PRSS4, TRY3, TRY4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+-->
-|DOMAIN=
+{{STRUCTURE_2r9p|  PDB=2r9p  |  SCENE=  }}
-|RELATEDENTRY=[[2ra3|2RA3]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r9p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r9p OCA], [http://www.ebi.ac.uk/pdbsum/2r9p PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2r9p RCSB]</span>
-}}
 '''Human mesotrypsin complexed with bovine pancreatic trypsin inhibitor(BPTI)'''
@@ Line 30: / Line 27: @@
 [[Category: Salameh, M A.]]
 [[Category: Soares, A S.]]
-[[Category: alternative splicing]]
+[[Category: Alternative splicing]]
-[[Category: bovine pancreatic trypsin inhibitor]]
+[[Category: Bovine pancreatic trypsin inhibitor]]
-[[Category: bpti]]
+[[Category: Bpti]]
-[[Category: calcium]]
+[[Category: Calcium]]
-[[Category: digestion]]
+[[Category: Digestion]]
-[[Category: human mesotrypsin]]
+[[Category: Human mesotrypsin]]
-[[Category: hydrolase]]
+[[Category: Hydrolase]]
-[[Category: hydrolase/hydrolase inhibitor complex]]
+[[Category: Hydrolase/hydrolase inhibitor complex]]
-[[Category: metal-binding]]
+[[Category: Metal-binding]]
-[[Category: pharmaceutical]]
+[[Category: Pharmaceutical]]
-[[Category: protease inhibitor]]
+[[Category: Protease inhibitor]]
-[[Category: secreted]]
+[[Category: Secreted]]
-[[Category: serine protease]]
+[[Category: Serine protease]]
-[[Category: serine protease inhibitor]]
+[[Category: Serine protease inhibitor]]
-[[Category: sulfation]]
+[[Category: Sulfation]]
-[[Category: zymogen]]
+[[Category: Zymogen]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 16:29:09 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:57:55 2008''