7AD7

Crystal structure of human complement C5 in complex with the K8 bovine knob domain peptide.

Summary for 7AD7

• Entry DOI: 10.2210/pdb7ad7/pdb
• Descriptor: Complement C5, K8 peptide, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: complement c5, c5, ultralong, ultra-long, knob domain., immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 384305.19

Authors

Macpherson, A.,van den Elsen, J.M.H.,Schulze, M.E.,Birtley, J.R. (deposition date: 2020-09-14, release date: 2021-03-10, Last modification date: 2024-01-31)

Primary citation

Macpherson, A.,Laabei, M.,Ahdash, Z.,Graewert, M.A.,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.,Lawson, A.D.,van den Elsen, J.M.
The allosteric modulation of Complement C5 by knob domain peptides.
Elife, 10:-, 2021

PubMed 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.

PubMed: 33570492
DOI: 10.7554/eLife.63586

Experimental method

X-RAY DIFFRACTION (2.3 Å)