5do2

From Proteopedia

(Difference between revisions)

Current revision

Complex structure of MERS-RBD bound with 4C2 antibody

Structural highlights

5do2 is a 6 chain structure with sequence from Middle East respiratory syndrome-related coronavirus and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.409Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

K0BRG7_MERS Spike protein S1: attaches the virion to the cell membrane by interacting with host receptor, initiating the infection.[HAMAP-Rule:MF_04099] Spike protein S2': Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099] Spike protein S2: mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.[HAMAP-Rule:MF_04099]

Publication Abstract from PubMed

The newly-emerging Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe and fatal acute respiratory disease in humans. Despite global efforts, the potential for an associated pandemic in the future cannot be excluded. The development of effective counter-measures is urgent. MERS-CoV-specific anti-viral drugs or vaccines are not yet available. Using the spike receptor-binding domain of MERS-CoV (MERS-RBD) to immunize mice, we identified two neutralizing monoclonal antibodies (mAbs) 4C2 and 2E6. Both mAbs potently bind to MERS-RBD and block virus entry in vitro with high efficacy. We further investigated their mechanisms of neutralization by crystallizing the complex between the Fab fragments and the RBD, and solved the structure of the 4C2 Fab/MERS-RBD complex. The structure showed that 4C2 recognizes an epitope that partially overlaps the receptor-binding footprint in MERS-RBD, thereby interfering with the virus/receptor interactions by both steric hindrance and interface-residue competition. 2E6 also blocks receptor binding, and competes with 4C2 for binding to MERS-RBD. Based on the structure, we further humanized 4C2 by preserving only the paratope residues and substituting the remaining amino acids with the counterparts from human immunoglobulins. The humanized 4C2 (4C2h) antibody sustained similar neutralizing activity and biochemical characteristics to the parental mouse antibody. Finally, we showed that 4C2h can significantly abate the virus titers in lungs of Ad5-hCD26-transduced mice infected with MERS-CoV, therefore representing a promising agent for prophylaxis and therapy in clinical settings.Cell Research advance online publication 22 September 2015; doi:10.1038/cr.2015.113.

A humanized neutralizing antibody against MERS-CoV targeting the receptor-binding domain of the spike protein.,Li Y, Wan Y, Liu P, Zhao J, Lu G, Qi J, Wang Q, Lu X, Wu Y, Liu W, Zhang B, Yuen KY, Perlman S, Gao GF, Yan J Cell Res. 2015 Sep 22. doi: 10.1038/cr.2015.113. PMID:26391698^[1]

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

References

↑ Li Y, Wan Y, Liu P, Zhao J, Lu G, Qi J, Wang Q, Lu X, Wu Y, Liu W, Zhang B, Yuen KY, Perlman S, Gao GF, Yan J. A humanized neutralizing antibody against MERS-CoV targeting the receptor-binding domain of the spike protein. Cell Res. 2015 Sep 22. doi: 10.1038/cr.2015.113. PMID:26391698 doi:http://dx.doi.org/10.1038/cr.2015.113

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5do2"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5do2 is ON HOLD
+==Complex structure of MERS-RBD bound with 4C2 antibody==
+<StructureSection load='5do2' size='340' side='right'caption='[[5do2]], [[Resolution|resolution]] 2.41&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5do2]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Middle_East_respiratory_syndrome-related_coronavirus Middle East respiratory syndrome-related coronavirus] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DO2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DO2 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.409&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=5do2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5do2 OCA], [https://pdbe.org/5do2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5do2 RCSB], [https://www.ebi.ac.uk/pdbsum/5do2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5do2 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/K0BRG7_MERS K0BRG7_MERS] Spike protein S1: attaches the virion to the cell membrane by interacting with host receptor, initiating the infection.[HAMAP-Rule:MF_04099]  Spike protein S2': Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099]  Spike protein S2: mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.[HAMAP-Rule:MF_04099]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The newly-emerging Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe and fatal acute respiratory disease in humans. Despite global efforts, the potential for an associated pandemic in the future cannot be excluded. The development of effective counter-measures is urgent. MERS-CoV-specific anti-viral drugs or vaccines are not yet available. Using the spike receptor-binding domain of MERS-CoV (MERS-RBD) to immunize mice, we identified two neutralizing monoclonal antibodies (mAbs) 4C2 and 2E6. Both mAbs potently bind to MERS-RBD and block virus entry in vitro with high efficacy. We further investigated their mechanisms of neutralization by crystallizing the complex between the Fab fragments and the RBD, and solved the structure of the 4C2 Fab/MERS-RBD complex. The structure showed that 4C2 recognizes an epitope that partially overlaps the receptor-binding footprint in MERS-RBD, thereby interfering with the virus/receptor interactions by both steric hindrance and interface-residue competition. 2E6 also blocks receptor binding, and competes with 4C2 for binding to MERS-RBD. Based on the structure, we further humanized 4C2 by preserving only the paratope residues and substituting the remaining amino acids with the counterparts from human immunoglobulins. The humanized 4C2 (4C2h) antibody sustained similar neutralizing activity and biochemical characteristics to the parental mouse antibody. Finally, we showed that 4C2h can significantly abate the virus titers in lungs of Ad5-hCD26-transduced mice infected with MERS-CoV, therefore representing a promising agent for prophylaxis and therapy in clinical settings.Cell Research advance online publication 22 September 2015; doi:10.1038/cr.2015.113.
-Authors: Li, Y., Wan, Y., Liu, P., Zhao, J., Lu, G., Qi, J., Wang, Q., Lu, X., Wu, Y., Liu, W., Yuen, K.Y., Perlman, S., Gao, G.F., Yan, J.
+A humanized neutralizing antibody against MERS-CoV targeting the receptor-binding domain of the spike protein.,Li Y, Wan Y, Liu P, Zhao J, Lu G, Qi J, Wang Q, Lu X, Wu Y, Liu W, Zhang B, Yuen KY, Perlman S, Gao GF, Yan J Cell Res. 2015 Sep 22. doi: 10.1038/cr.2015.113. PMID:26391698<ref>PMID:26391698</ref>
-Description: Complex structure of MERS-RBD bound with 4C2 antibody
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Yuen, K.Y]]
+<div class="pdbe-citations 5do2" style="background-color:#fffaf0;"></div>
-[[Category: Gao, G.F]]
-[[Category: Li, Y]]
+==See Also==
-[[Category: Liu, P]]
+*[[Sandbox 3001|Sandbox 3001]]
-[[Category: Wu, Y]]
+*[[Spike protein 3D structures|Spike protein 3D structures]]
-[[Category: Lu, G]]
+== References ==
-[[Category: Wan, Y]]
+<references/>
-[[Category: Zhao, J]]
+__TOC__
-[[Category: Lu, X]]
+</StructureSection>
-[[Category: Perlman, S]]
+[[Category: Large Structures]]
-[[Category: Liu, W]]
+[[Category: Middle East respiratory syndrome-related coronavirus]]
-[[Category: Wang, Q]]
+[[Category: Mus musculus]]
-[[Category: Yan, J]]
+[[Category: Gao GF]]
-[[Category: Qi, J]]
+[[Category: Li Y]]
+[[Category: Liu P]]
+[[Category: Liu W]]
+[[Category: Lu G]]
+[[Category: Lu X]]
+[[Category: Perlman S]]
+[[Category: Qi J]]
+[[Category: Wan Y]]
+[[Category: Wang Q]]
+[[Category: Wu Y]]
+[[Category: Yan J]]
+[[Category: Yuen KY]]
+[[Category: Zhao J]]

5do2

From Proteopedia

Current revision

Complex structure of MERS-RBD bound with 4C2 antibody

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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