2r0l
From Proteopedia
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|PDB= 2r0l |SIZE=350|CAPTION= <scene name='initialview01'>2r0l</scene>, resolution 2.20Å | |PDB= 2r0l |SIZE=350|CAPTION= <scene name='initialview01'>2r0l</scene>, resolution 2.20Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= HGFAC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= HGFAC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1ybw|1YBW]], [[1yc0|1YC0]], [[2r0k|2R0K]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r0l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r0l OCA], [http://www.ebi.ac.uk/pdbsum/2r0l PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2r0l RCSB]</span> | ||
}} | }} | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:55:21 2008'' |
Revision as of 01:55, 31 March 2008
| |||||||
| , resolution 2.20Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Gene: | HGFAC (Homo sapiens) | ||||||
| Related: | 1YBW, 1YC0, 2R0K
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Short Form HGFA with Inhibitory Fab75
Overview
To better understand how the relatively flat antigen-combining sites of antibodies interact with the concave shaped substrate-binding clefts of proteases, we determined the structures of two antibodies in complex with the trypsin-like hepatocyte growth-factor activator (HGFA). The two inhibitory antibodies, Ab58 and Ab75, were generated from a human Fab phage display library with synthetic diversity in the three complementarity determining regions (H1, H2, and H3) of the heavy chain, mimicking the natural diversity of the human Ig repertoire. Biochemical studies and the structures of the Fab58:HGFA (3.5-A resolution) and the Fab75:HGFA (2.2-A resolution) complexes revealed that Ab58 obstructed substrate access to the active site, whereas Ab75 allosterically inhibited substrate hydrolysis. In both cases, the antibodies interacted with the same protruding element (99-loop), which forms part of the substrate-binding cleft. Ab58 inserted its H1 and H2 loops in the cleft to occupy important substrate interaction sites (S3 and S2). In contrast, Ab75 bound at the backside of the cleft to a region corresponding to thrombin exosite II, which is known to interact with allosteric effector molecules. In agreement with the structural analysis, binding assays with active site inhibitors and enzymatic assays showed that Ab58 is a competitive inhibitor, and Ab75 is a partial competitive inhibitor. These results provide structural insight into antibody-mediated protease inhibition. They suggest that unlike canonical inhibitors, antibodies may preferentially target protruding loops at the rim of the substrate-binding cleft to interfere with the catalytic machinery of proteases without requiring long insertion loops.
About this Structure
2R0L is a Protein complex structure of sequences from [1] and Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural insight into distinct mechanisms of protease inhibition by antibodies., Wu Y, Eigenbrot C, Liang WC, Stawicki S, Shia S, Fan B, Ganesan R, Lipari MT, Kirchhofer D, Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19784-9. Epub 2007 Dec 5. PMID:18077410 [[Category: ]]
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