Journal Article

PUBDB-2021-04339

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The allosteric modulation of complement C5 by knob domain peptides

Macpherson, A. (Corresponding author) ; Laabei, M. ; Ahdash, Z. ; Graewert, M. A.EMBL* ; Birtley, J. R. ; Schulze, M. E. ; Crennell, S. ; Robinson, S. A. ; Holmes, B. ; Oleinikovas, V. ; Nilsson, P. H. ; Snowden, J. ; Ellis, V. ; Mollnes, T. E. ; Deane, C. M. ; Svergun, D.EMBL* ; Lawson, A. D. ; van den Elsen, J. M. (Corresponding author)

2021
eLife Sciences Publications Cambridge

This record in other databases:        

Please use a persistent id in citations: doi:10.7554/eLife.63586  doi:10.3204/PUBDB-2021-04339

Abstract: Bovines have evolved a subset of antibodies with ultra-long heavy chain complementarity determining regions that harbour cysteine-rich knob domains. To produce high-affinity peptides, we previously isolated autonomous 3–6 kDa knob domains from bovine antibodies. Here, we show that binding of four knob domain peptides elicits a range of effects on the clinically validated drug target complement C5. Allosteric mechanisms predominated, with one peptide selectively inhibiting C5 cleavage by the alternative pathway C5 convertase, revealing a targetable mechanistic difference between the classical and alternative pathway C5 convertases. Taking a hybrid biophysical approach, we present C5-knob domain co-crystal structures and, by solution methods, observed allosteric effects propagating >50 Å from the binding sites. This study expands the therapeutic scope of C5, presents new inhibitors, and introduces knob domains as new, low molecular weight antibody fragments, with therapeutic potential.

---

Contributing Institute(s):

1. EMBL-User (EMBL-User)
2. EMBL (EMBL)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2021

---

Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---