This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

6bx8

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 07:43, 10 April 2019

Human Mesotrypsin (PRSS3) Complexed with Tissue Factor Pathway Inhibitor Variant (TFPI1-KD1-K15R-I17C-I34C)

Structural highlights

6bx8 is a 8 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:	6har
Gene:	PRSS3, PRSS4, TRY3, TRY4 (HUMAN), TFPI, LACI, TFPI1 (HUMAN)
Activity:	Trypsin, with EC number 3.4.21.4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TRY3_HUMAN] Digestive protease specialized for the degradation of trypsin inhibitors. In the ileum, may be involved in defensin processing, including DEFA5.^[1] ^[2] [TFPI1_HUMAN] Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex. It possesses an antithrombotic action and also the ability to associate with lipoproteins in plasma.

Publication Abstract from PubMed

Serine protease inhibitors of the Kunitz-bovine pancreatic trypsin inhibitor (BPTI) family are ubiquitous biological regulators of proteolysis. These small proteins are resistant to proteolysis, but can be slowly cleaved within the protease binding loop by target proteases, thereby compromising their activity. For the human protease, mesotrypsin, this cleavage is especially rapid. Here, we aimed to stabilize the Kunitz domain structure against proteolysis through disulfide engineering. Substitution within the Kunitz inhibitor domain of the amyloid precursor protein (APPI) that incorporated a new disulfide bond between residues 17 and 34 reduced proteolysis by mesotrypsin 54-fold. Similar disulfide engineering of tissue factor pathway inhibitor-1 Kunitz domain 1 (KD1TFPI1) and bikunin Kunitz domain 2 (KD2bikunin) likewise stabilized these inhibitors against mesotrypsin proteolysis 17-fold and 6.6-fold, respectively. Crystal structures of disulfide-engineered APPI and KD1TFPI1 variants in a complex with mesotrypsin at 1.5 A and 2.0 A resolution, respectively, confirmed the formation of well-ordered disulfide bonds positioned to stabilize the binding loop. Long all-atom molecular dynamics simulations of disulfide-engineered Kunitz domains and their complexes with mesotrypsin revealed conformational stabilization of the primed side of the inhibitor binding loop by the engineered disulfide, along with global suppression of conformational dynamics in the Kunitz domain. Our findings suggest that the Cys17-Cys34 disulfide slows proteolysis by dampening conformational fluctuations in the binding loop and minimizing motion at the enzyme-inhibitor interface. The generalizable approach developed here for the stabilization against proteolysis of Kunitz domains, which can serve as important scaffolds for therapeutics, may thus find applications in drug development.

Disulfide engineering of human Kunitz-type serine protease inhibitors enhances proteolytic stability and target affinity toward mesotrypsin.,Cohen I, Coban M, Shahar A, Sankaran B, Hockla A, Lacham S, Caulfield TR, Radisky ES, Papo N J Biol Chem. 2019 Jan 30. pii: RA118.007292. doi: 10.1074/jbc.RA118.007292. PMID:30700553^[3]

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

References

↑ Ghosh D, Porter E, Shen B, Lee SK, Wilk D, Drazba J, Yadav SP, Crabb JW, Ganz T, Bevins CL. Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol. 2002 Jun;3(6):583-90. Epub 2002 May 20. PMID:12021776 doi:10.1038/ni797
↑ Szmola R, Kukor Z, Sahin-Toth M. Human mesotrypsin is a unique digestive protease specialized for the degradation of trypsin inhibitors. J Biol Chem. 2003 Dec 5;278(49):48580-9. Epub 2003 Sep 24. PMID:14507909 doi:10.1074/jbc.M310301200
↑ Cohen I, Coban M, Shahar A, Sankaran B, Hockla A, Lacham S, Caulfield TR, Radisky ES, Papo N. Disulfide engineering of human Kunitz-type serine protease inhibitors enhances proteolytic stability and target affinity toward mesotrypsin. J Biol Chem. 2019 Jan 30. pii: RA118.007292. doi: 10.1074/jbc.RA118.007292. PMID:30700553 doi:http://dx.doi.org/10.1074/jbc.RA118.007292

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6bx8"

@@ Line 1: / Line 1: @@
 ==Human Mesotrypsin (PRSS3) Complexed with Tissue Factor Pathway Inhibitor Variant (TFPI1-KD1-K15R-I17C-I34C)==
-<StructureSection load='6bx8' size='340' side='right' caption='[[6bx8]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
+<StructureSection load='6bx8' size='340' side='right'caption='[[6bx8]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6bx8]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BX8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BX8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6bx8]] is a 8 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=6BX8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BX8 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6har|6har]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PRSS3, PRSS4, TRY3, TRY4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), TFPI, LACI, TFPI1 ([http://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'>[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></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bx8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bx8 OCA], [http://pdbe.org/6bx8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bx8 RCSB], [http://www.ebi.ac.uk/pdbsum/6bx8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bx8 ProSAT]</span></td></tr>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Trypsin]]
 [[Category: Coban, M]]

6bx8

From Proteopedia

Revision as of 07:43, 10 April 2019

Human Mesotrypsin (PRSS3) Complexed with Tissue Factor Pathway Inhibitor Variant (TFPI1-KD1-K15R-I17C-I34C)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox