6pyd

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<StructureSection load='6pyd' size='340' side='right'caption='[[6pyd]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='6pyd' size='340' side='right'caption='[[6pyd]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6pyd]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PYD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PYD FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6pyd]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PYD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PYD FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=P4S:(3beta,5beta,14alpha,15beta)-3,5-dihydroxy-14,15-epoxybufa-20,22-dienolide'>P4S</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=P4S:(3beta,5beta,14alpha,15beta)-3,5-dihydroxy-14,15-epoxybufa-20,22-dienolide'>P4S</scene></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=6pyd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pyd OCA], [http://pdbe.org/6pyd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pyd RCSB], [http://www.ebi.ac.uk/pdbsum/6pyd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pyd ProSAT]</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=6pyd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pyd OCA], [http://pdbe.org/6pyd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pyd RCSB], [http://www.ebi.ac.uk/pdbsum/6pyd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pyd ProSAT]</span></td></tr>
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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BACKGROUND: Levels of marinobufagenin (MBG), an endogenous bufadienolide Na/K-ATPase (NKA) inhibitor, increase in preeclampsia and in NaCl-sensitive hypertension. METHODS: We tested a 3E9 monoclonal anti-MBG antibody (mAb) for the ability to lower blood pressure (BP) in NaCl-sensitive hypertension and to reverse the preeclampsia-induced inhibition of erythrocyte NKA. Measurements of MBG were performed via immunoassay based on 4G4 anti-MBG mAb. RESULTS: In hypertensive Dahl-S rats, intraperitoneal administration of 50 microg/kg 3E9 mAb lowered BP by 32 mmHg and activated the Na/K-pump in the thoracic aorta by 51%. NaCl supplementation of pregnant rats (n = 16) produced a 37 mmHg increase in BP, a 3.5-fold rise in MBG excretion, and a 25% inhibition of the Na/K-pump in the thoracic aorta, compared with pregnant rats on a normal NaCl intake. In eight pregnant hypertensive rats, 3E9 mAb reduced the BP (21 mmHg) and restored the vascular Na/K-pump. In 14 patients with preeclampsia (mean BP, 126 +/- 3 mmHg; 26.9 +/- 1.4 years; gestational age, 37 +/- 0.8 weeks), plasma MBG was increased three-fold and erythrocyte NKA was inhibited compared with that of 12 normotensive pregnant women (mean BP, 71 +/- 3 mmHg) (1.5 +/- 0.1 vs. 3.1 +/- 0.2 micromol Pi/ml/h, respectively; P &lt; 0.01). Ex-vivo 3E9 mAb restored NKA activity in erythrocytes from patients with preeclampsia. As compared with 3E9 mAb, Digibind, an affinity-purified antidigoxin antibody, was less active with respect to lowering BP in both hypertensive models and to restoration of NKA from erythrocytes from patients with preeclampsia. CONCLUSION: Anti-MBG mAbs may be a useful tool in studies of MBG in vitro and in vivo and may offer treatment of preeclampsia.
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We describe a Kappa-on-Heavy (KoH) mouse that produces a class of highly diverse, fully human, antibody-like agents. This mouse was made by replacing the germline variable sequences of both the Ig heavy-chain (IgH) and Ig kappa (IgK) loci with the human IgK germline variable sequences, producing antibody-like molecules with an antigen binding site made up of 2 kappa variable domains. These molecules, named KoH bodies, structurally mimic naturally existing Bence-Jones light-chain dimers in their variable domains and remain wild-type in their antibody constant domains. Unlike artificially diversified, nonimmunoglobulin alternative scaffolds (e.g., DARPins), KoH bodies consist of a configuration of normal Ig scaffolds that undergo natural diversification in B cells. Monoclonal KoH bodies have properties similar to those of conventional antibodies but exhibit an enhanced ability to bind small molecules such as the endogenous cardiotonic steroid marinobufagenin (MBG) and nicotine. A comparison of crystal structures of MBG bound to a KoH Fab versus a conventional Fab showed that the KoH body has a much deeper binding pocket, allowing MBG to be held 4 A further down into the combining site between the 2 variable domains.
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Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension.,Fedorova OV, Simbirtsev AS, Kolodkin NI, Kotov AY, Agalakova NI, Kashkin VA, Tapilskaya NI, Bzhelyansky A, Reznik VA, Frolova EV, Nikitina ER, Budny GV, Longo DL, Lakatta EG, Bagrov AY J Hypertens. 2008 Dec;26(12):2414-25. doi: 10.1097/HJH.0b013e328312c86a. PMID:19008721<ref>PMID:19008721</ref>
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Kappa-on-Heavy (KoH) bodies are a distinct class of fully-human antibody-like therapeutic agents with antigen-binding properties.,Macdonald LE, Meagher KA, Franklin MC, Levenkova N, Hansen J, Badithe AT, Zhong M, Krueger P, Rafique A, Tu N, Shevchuk J, Wadhwa S, Ehrlich G, Bautista J, Grant C, Esau L, Poueymirou WT, Auerbach W, Morton L, Babb R, Chen G, Huang T, MacDonald D, Graham K, Gurer C, Voronina VA, McWhirter JR, Guo C, Yancopoulos GD, Murphy AJ Proc Natl Acad Sci U S A. 2019 Dec 26. pii: 1901734117. doi:, 10.1073/pnas.1901734117. PMID:31879340<ref>PMID:31879340</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Lk3 transgenic mice]]
[[Category: Franklin, M C]]
[[Category: Franklin, M C]]
[[Category: Macdonald, L E]]
[[Category: Macdonald, L E]]

Revision as of 09:42, 8 January 2020

Structure of 3E9 antibody Fab bound to marinobufagenin

PDB ID 6pyd

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