3t2n: Difference between revisions

Latest revision as of 10:27, 6 November 2024

Human hepsin protease in complex with the Fab fragment of an inhibitory antibody

Structural highlights

3t2n is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.55Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HEPS_HUMAN Plays an essential role in cell growth and maintenance of cell morphology. May mediate the activating cleavage of HGF and MST1/HGFL.^[1] ^[2]

Publication Abstract from PubMed

Hepsin is a type II transmembrane serine protease that is expressed in several human tissues. Overexpression of hepsin has been found to correlate with tumor progression and metastasis, which is so far best studied for prostate cancer, where more than 90% of such tumors show this characteristic. To enable improved future patient treatment, we developed a monoclonal humanized antibody that selectively inhibits human hepsin and does not inhibit other related proteases. We found that our antibody hH35 potently inhibits hepsin enzymatic activity at nanomolar concentrations. Kinetic characterization revealed non-linear, slow, tight-binding inhibition. This correlates with the crystal structure we obtained for the human hepsin-hH35 antibody Fab fragment complex, which showed that the antibody binds hepsin around a3-helix, located far from the active center. The unique allosteric mode of inhibition of hH35 is distinct from the recently described HGFA (Hepatocyte Growth Factor Activator) allosteric antibody inhibition. We further explain how a small change in the antibody design induces dramatic structural rearrangements in the hepsin antigen upon binding leading to complete enzyme inactivation.

Allosteric antibody inhibition of human Hepsin protease.,Koschubs T, Dengl S, Duerr H, Kaluza K, Georges G, Hartl C, Jennewein S, Lanzendoerfer M, Auer J, Stern A, Huang KS, Packman K, Gubler U, Kostrewa D, Ries S, Hansen S, Kohnert U, Cramer P, Mundigl O Biochem J. 2011 Dec 2. PMID:22132769^[3]

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

References

↑ Ganesan R, Kolumam GA, Lin SJ, Xie MH, Santell L, Wu TD, Lazarus RA, Chaudhuri A, Kirchhofer D. Proteolytic activation of pro-macrophage-stimulating protein by hepsin. Mol Cancer Res. 2011 Sep;9(9):1175-86. doi: 10.1158/1541-7786.MCR-11-0004. Epub, 2011 Aug 29. PMID:21875933 doi:https://dx.doi.org/10.1158/1541-7786.MCR-11-0004
↑ Herter S, Piper DE, Aaron W, Gabriele T, Cutler G, Cao P, Bhatt AS, Choe Y, Craik CS, Walker N, Meininger D, Hoey T, Austin RJ. Hepatocyte growth factor is a preferred in vitro substrate for human hepsin, a membrane-anchored serine protease implicated in prostate and ovarian cancers. Biochem J. 2005 Aug 15;390(Pt 1):125-36. PMID:15839837 doi:10.1042/BJ20041955
↑ Koschubs T, Dengl S, Duerr H, Kaluza K, Georges G, Hartl C, Jennewein S, Lanzendoerfer M, Auer J, Stern A, Huang KS, Packman K, Gubler U, Kostrewa D, Ries S, Hansen S, Kohnert U, Cramer P, Mundigl O. Allosteric antibody inhibition of human Hepsin protease. Biochem J. 2011 Dec 2. PMID:22132769 doi:10.1042/BJ20111317

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Ganesan R, Kolumam GA, Lin SJ, Xie MH, Santell L, Wu TD, Lazarus RA, Chaudhuri A, Kirchhofer D. Proteolytic activation of pro-macrophage-stimulating protein by hepsin. Mol Cancer Res. 2011 Sep;9(9):1175-86. doi: 10.1158/1541-7786.MCR-11-0004. Epub, 2011 Aug 29. PMID:21875933 doi:https://dx.doi.org/10.1158/1541-7786.MCR-11-0004

[2] Herter S, Piper DE, Aaron W, Gabriele T, Cutler G, Cao P, Bhatt AS, Choe Y, Craik CS, Walker N, Meininger D, Hoey T, Austin RJ. Hepatocyte growth factor is a preferred in vitro substrate for human hepsin, a membrane-anchored serine protease implicated in prostate and ovarian cancers. Biochem J. 2005 Aug 15;390(Pt 1):125-36. PMID:15839837 doi:10.1042/BJ20041955

[3] Koschubs T, Dengl S, Duerr H, Kaluza K, Georges G, Hartl C, Jennewein S, Lanzendoerfer M, Auer J, Stern A, Huang KS, Packman K, Gubler U, Kostrewa D, Ries S, Hansen S, Kohnert U, Cramer P, Mundigl O. Allosteric antibody inhibition of human Hepsin protease. Biochem J. 2011 Dec 2. PMID:22132769 doi:10.1042/BJ20111317

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='3t2n' size='340' side='right'caption='[[3t2n]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3t2n]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T2N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T2N FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3t2n]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T2N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T2N FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1z8g|1z8g]], [[1o5e|1o5e]], [[1p57|1p57]]</div></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.55&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HPN, TMPRSS1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Hepsin Hepsin], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.106 3.4.21.106] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3t2n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t2n OCA], [https://pdbe.org/3t2n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t2n RCSB], [https://www.ebi.ac.uk/pdbsum/3t2n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t2n ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/HEPS_HUMAN HEPS_HUMAN]] Plays an essential role in cell growth and maintenance of cell morphology. May mediate the activating cleavage of HGF and MST1/HGFL.<ref>PMID:21875933</ref> <ref>PMID:15839837</ref>
+[https://www.uniprot.org/uniprot/HEPS_HUMAN HEPS_HUMAN] Plays an essential role in cell growth and maintenance of cell morphology. May mediate the activating cleavage of HGF and MST1/HGFL.<ref>PMID:21875933</ref> <ref>PMID:15839837</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Hepsin]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Auer, J]]
+[[Category: Auer J]]
-[[Category: Cramer, P]]
+[[Category: Cramer P]]
-[[Category: Dengl, S]]
+[[Category: Dengl S]]
-[[Category: Duerr, H]]
+[[Category: Duerr H]]
-[[Category: Georges, G]]
+[[Category: Georges G]]
-[[Category: Hansen, S]]
+[[Category: Hansen S]]
-[[Category: Hartl, C]]
+[[Category: Hartl C]]
-[[Category: Huang, K S]]
+[[Category: Huang K-S]]
-[[Category: Jennewein, S]]
+[[Category: Jennewein S]]
-[[Category: Kaluza, K]]
+[[Category: Kaluza K]]
-[[Category: Kohnert, U]]
+[[Category: Kohnert U]]
-[[Category: Koschubs, T]]
+[[Category: Koschubs T]]
-[[Category: Kostrewa, D]]
+[[Category: Kostrewa D]]
-[[Category: Lanzendoerfer, M]]
+[[Category: Lanzendoerfer M]]
-[[Category: Mundigl, O]]
+[[Category: Mundigl O]]
-[[Category: Ries, S]]
+[[Category: Ries S]]
-[[Category: Stern, A]]
+[[Category: Stern A]]
-[[Category: Hydrolase]]
-[[Category: Laminin-332]]
-[[Category: Pro-hgf]]
-[[Category: Srcr domain]]
-[[Category: Substrates include pro-hepsin]]
-[[Category: Transmembrane]]
-[[Category: Type ii transmembrane serine protease]]

3t2n: Difference between revisions

Latest revision as of 10:27, 6 November 2024

Human hepsin protease in complex with the Fab fragment of an inhibitory antibody

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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