View source for 7b2q


==Cryo-EM structure of complement C4b in complex with nanobody B12==
<StructureSection load='7b2q' size='340' side='right'caption='[[7b2q]], [[Resolution|resolution]] 3.76&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7b2q]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7B2Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B2Q FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.76&#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=7b2q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b2q OCA], [https://pdbe.org/7b2q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b2q RCSB], [https://www.ebi.ac.uk/pdbsum/7b2q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b2q ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CO4A_HUMAN CO4A_HUMAN] Defects in C4A are the cause of complement component 4A deficiency (C4AD) [MIM:[https://omim.org/entry/614380 614380]. A rare defect of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus with or without associated glomerulonephritis.<ref>PMID:8473511</ref>   Defects in C4A are a cause of susceptibility to systemic lupus erythematosus (SLE) [MIM:[https://omim.org/entry/152700 152700]. A chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system. Note=Interindividual copy-number variation (CNV) of complement component C4 and associated polymorphisms result in different susceptibilities to SLE. The risk of SLE susceptibility has been shown to be significantly increased among subjects with only two copies of total C4. A high copy number is a protective factor against SLE.<ref>PMID:17503323</ref> 
== Function ==
[https://www.uniprot.org/uniprot/CO4A_HUMAN CO4A_HUMAN] C4 plays a central role in the activation of the classical pathway of the complement system. It is processed by activated C1 which removes from the alpha chain the C4a anaphylatoxin. The remaining alpha chain fragment C4b is the major activation product and is an essential subunit of the C3 convertase (C4b2a) and the C5 convertase (C3bC4b2a) enzymes of the classical complement pathway.  Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.
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== Publication Abstract from PubMed ==
Cleavage of the mammalian plasma protein C4 into C4b initiates opsonization, lysis, and clearance of microbes and damaged host cells by the classical and lectin pathways of the complement system. Dysregulated activation of C4 and other initial components of the classical pathway may cause or aggravate pathologies, such as systemic lupus erythematosus, Alzheimer disease, and schizophrenia. Modulating the activity of C4b by small-molecule or protein-based inhibitors may represent a promising therapeutic approach for preventing excessive inflammation and damage to host cells and tissue. Here, we present seven nanobodies, derived from llama (Lama glama) immunization, that bind to human C4b (Homo sapiens) with high affinities ranging from 3.2 nM to 14 pM. The activity of the nanobodies varies from no to complete inhibition of the classical pathway. The inhibiting nanobodies affect different steps in complement activation, in line with blocking sites for proconvertase formation, C3 substrate binding to the convertase, and regulator-mediated inactivation of C4b. For four nanobodies, we determined single-particle cryo-electron microscopy structures in complex with C4b at 3.4-4 A resolution. The structures rationalize the observed functional effects of the nanobodies and define their mode of action during complement activation. Thus, we characterized seven anti-C4b nanobodies with diverse effects on the classical pathway of complement activation that may be explored for imaging, diagnostic, or therapeutic applications.

Multifaceted Activities of Seven Nanobodies against Complement C4b.,De la O Becerra KI, Oosterheert W, van den Bos RM, Xenaki KT, Lorent JH, Ruyken M, Schouten A, Rooijakkers SHM, van Bergen En Henegouwen PMP, Gros P J Immunol. 2022 May 1;208(9):2207-2219. doi: 10.4049/jimmunol.2100647. Epub 2022 , Apr 15. PMID:35428691<ref>PMID:35428691</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7b2q" style="background-color:#fffaf0;"></div>

==See Also==
*[[Complement C4|Complement C4]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Lama glama]]
[[Category: Large Structures]]
[[Category: De la O Becerra KI]]
[[Category: Gros P]]
[[Category: Oosterheert W]]