View source for 7op0


==Crystal structure of complement C5 in complex with chemically synthesized K92 knob domain.==
<StructureSection load='7op0' size='340' side='right'caption='[[7op0]], [[Resolution|resolution]] 2.57&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7op0]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OP0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OP0 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]] 2.57&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <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=7op0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7op0 OCA], [https://pdbe.org/7op0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7op0 RCSB], [https://www.ebi.ac.uk/pdbsum/7op0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7op0 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CO5_HUMAN CO5_HUMAN] Defects in C5 are the cause of complement component 5 deficiency (C5D) [MIM:[https://omim.org/entry/609536 609536]. A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis.  Note=An association study of C5 haplotypes and genotypes in individuals with chronic hepatitis C virus infection shows that individuals homozygous for the C5_1 haplotype have a significantly higher stage of liver fibrosis than individuals carrying at least 1 other allele (PubMed:15995705).
== Function ==
[https://www.uniprot.org/uniprot/CO5_HUMAN CO5_HUMAN] Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled.  Derived from proteolytic degradation of complement C5, C5 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. C5a also stimulates the locomotion of polymorphonuclear leukocytes (chemokinesis) and direct their migration toward sites of inflammation (chemotaxis).
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== Publication Abstract from PubMed ==
Cysteine-rich knob domains found in the ultralong complementarity determining regions of a subset of bovine antibodies are capable of functioning autonomously as 3-6 kDa peptides. While they can be expressed recombinantly in cellular systems, in this paper we show that knob domains are also readily amenable to a chemical synthesis, with a co-crystal structure of a chemically synthesized knob domain in complex with an antigen showing structural equivalence to the biological product. For drug discovery, following the immunization of cattle, knob domain peptides can be synthesized directly from antibody sequence data, combining the power and diversity of the bovine immune repertoire with the ability to rapidly incorporate nonbiological modifications. We demonstrate that, through rational design with non-natural amino acids, a paratope diversity can be massively expanded, in this case improving the efficacy of an allosteric peptide. As a potential route to further improve stability, we also performed head-to-tail cyclizations, exploiting the proximity of the N and C termini to synthesize functional, fully cyclic antibody fragments. Lastly, we highlight the stability of knob domains in plasma and, through pharmacokinetic studies, use palmitoylation as a route to extend the plasma half-life of knob domains in vivo. This study presents an antibody-derived medicinal chemistry platform, with protocols for solid-phase synthesis of knob domains, together with the characterization of their molecular structures, in vitro pharmacology, and pharmacokinetics.

The Chemical Synthesis of Knob Domain Antibody Fragments.,Macpherson A, Birtley JR, Broadbridge RJ, Brady K, Schulze MED, Tang Y, Joyce C, Saunders K, Bogle G, Horton J, Kelm S, Taylor RD, Franklin RJ, Selby MD, Laabei M, Wonfor T, Hold A, Stanley P, Vadysirisack D, Shi J, van den Elsen J, Lawson ADG ACS Chem Biol. 2021 Sep 17;16(9):1757-1769. doi: 10.1021/acschembio.1c00472. Epub , 2021 Aug 18. PMID:34406751<ref>PMID:34406751</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 7op0" style="background-color:#fffaf0;"></div>

==See Also==
*[[Complement C5 3D structures|Complement C5 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Birtley JR]]
[[Category: Macpherson A]]
[[Category: Schulze ME]]
[[Category: Van der Elsen JMH]]