6gwn

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of Stabilized Active Plasminogen Activator Inhibitor-1 (PAI-1-W175F) in Complex with Two Inhibitory Nanobodies (VHH-2g-42, VHH-2w-64)

Structural highlights

6gwn is a 3 chain structure with sequence from Homo sapiens and Vicugna pacos. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.03Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasminogen activators (PAs) tissue-type PA (tPA) and urokinase-type PA (uPA) plays a crucial role in many (patho)physiological processes, e.g. cardiovascular disease, tissue fibrosis, as well as in many age-related pathologies. Therefore, much effort has been put into the development of small molecule or antibody-based PAI-1 inhibitors. OBJECTIVE: To elucidate the molecular mechanism of nanobody-induced PAI-1 inhibition. METHODS AND RESULTS: Here we present the first crystal structures of PAI-1 in complex with two neutralizing nanobodies (Nbs). These structures, together with biochemical and biophysical characterization, reveal that Nb VHH-2g-42 (Nb42) interferes with the initial PAI-1/PA complex formation, whereas VHH-2w-64 (Nb64) redirects the PAI-1/PA interaction to PAI-1 deactivation and regeneration of active PA. Furthermore, whereas vitronectin (Vn) does not have an impact on the inhibitory effect of Nb42, it strongly potentiates the inhibitory effect of Nb64, which may contribute to a strong inhibitory potential of Nb64 in vivo. CONCLUSIONS: These findings illuminate the molecular mechanisms of PAI-1 inhibition. Nb42 and Nb64 can be used as starting points to engineer further improved antibody-based PAI-1 inhibitors or guide the rational design of small molecule inhibitors to treat a wide range of PAI-1-related pathophysiological conditions.

Molecular mechanism of two nanobodies that inhibit PAI-1 activity reveals a modulation at distinct stages of the PAI-1/plasminogen activator interaction.,Sillen M, Weeks SD, Zhou X, Komissarov AA, Florova G, Idell S, Strelkov SV, Declerck PJ J Thromb Haemost. 2019 Dec 19. doi: 10.1111/jth.14716. PMID:31858714^[1]

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

References

↑ Sillen M, Weeks SD, Zhou X, Komissarov AA, Florova G, Idell S, Strelkov SV, Declerck PJ. Molecular mechanism of two nanobodies that inhibit PAI-1 activity reveals a modulation at distinct stages of the PAI-1/plasminogen activator interaction. J Thromb Haemost. 2019 Dec 19. doi: 10.1111/jth.14716. PMID:31858714 doi:http://dx.doi.org/10.1111/jth.14716

1 Structural highlights
2 Publication Abstract from PubMed
3 See Also
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 3: / Line 3: @@
 <StructureSection load='6gwn' size='340' side='right'caption='[[6gwn]], [[Resolution|resolution]] 2.03&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6gwn]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Alpaca Alpaca] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GWN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GWN FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6gwn]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Vicugna_pacos Vicugna pacos]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GWN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6GWN FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SERPINE1, PAI1, PLANH1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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]] 2.03&#8491;</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=6gwn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gwn OCA], [http://pdbe.org/6gwn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gwn RCSB], [http://www.ebi.ac.uk/pdbsum/6gwn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gwn ProSAT]</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=6gwn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gwn OCA], [https://pdbe.org/6gwn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6gwn RCSB], [https://www.ebi.ac.uk/pdbsum/6gwn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6gwn ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[http://www.uniprot.org/uniprot/PAI1_HUMAN PAI1_HUMAN]] Defects in SERPINE1 are the cause of plasminogen activator inhibitor-1 deficiency (PAI-1D) [MIM:[http://omim.org/entry/613329 613329]]. It is a hematologic disorder characterized by increased bleeding after trauma, injury, or surgery. Affected females have menorrhagia. The bleeding defect is due to increased fibrinolysis of fibrin blood clots due to deficiency of plasminogen activator inhibitor-1, which inhibits tissue and urinary activators of plasminogen.<ref>PMID:9207454</ref>   Note=High concentrations of SERPINE1 seem to contribute to the development of venous but not arterial occlusions.
-== Function ==
-[[http://www.uniprot.org/uniprot/PAI1_HUMAN PAI1_HUMAN]] Serine protease inhibitor. This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, protein C and matriptase-3/TMPRSS7. Its rapid interaction with PLAT may function as a major control point in the regulation of fibrinolysis.<ref>PMID:15853774</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 16: @@
 </div>
 <div class="pdbe-citations 6gwn" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Antibody 3D structures|Antibody 3D structures]]
+*[[Plasminogen activator inhibitor|Plasminogen activator inhibitor]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Alpaca]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Declerck, P J]]
+[[Category: Vicugna pacos]]
-[[Category: Sillen, M]]
+[[Category: Declerck PJ]]
-[[Category: Strelkov, S V]]
+[[Category: Sillen M]]
-[[Category: Weeks, S D]]
+[[Category: Strelkov SV]]
-[[Category: Antibody fragment]]
+[[Category: Weeks SD]]
-[[Category: Hydrolase]]
-[[Category: Nanobody]]
-[[Category: Pai-1]]
-[[Category: Pai-1-w175f]]
-[[Category: Plasminogen activator inhibitor-1]]
-[[Category: Protease inhibitor]]
-[[Category: Protein complex]]
-[[Category: Serine protease inhibitor]]
-[[Category: Serpin]]

6gwn

From Proteopedia

Current revision

Crystal Structure of Stabilized Active Plasminogen Activator Inhibitor-1 (PAI-1-W175F) in Complex with Two Inhibitory Nanobodies (VHH-2g-42, VHH-2w-64)

Structural highlights

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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