The allosteric modulation of complement C5 by knob domain peptides

Alex Macpherson; Maisem Laabei; Zainab Ahdash; Melissa A Graewert; James R Birtley; Monika-Sarah Ed Schulze; Susan Crennell; Sarah A Robinson; Ben Holmes; Vladas Oleinikovas; Per H Nilsson; James Snowden; Victoria Ellis; Tom Eirik Mollnes; Charlotte M Deane; Dmitri Svergun; Alastair Dg Lawson; Jean Mh van den Elsen

doi:10.7554/eLife.63586

The allosteric modulation of complement C5 by knob domain peptides

Alex Macpherson^*, Maisem Laabei, Zainab Ahdash, Melissa A Graewert, James R Birtley, Monika-Sarah Ed Schulze, Susan Crennell, Sarah A Robinson, Ben Holmes, Vladas Oleinikovas, Per H Nilsson, James Snowden, Victoria Ellis, Tom Eirik Mollnes, Charlotte M Deane, Dmitri Svergun, Alastair Dg Lawson, Jean Mh van den Elsen^*

^*Corresponding author for this work

School of Cellular and Molecular Medicine

Research output: Contribution to journal › Article (Academic Journal) › peer-review

21 Citations (Scopus)

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.

Original language	English
Article number	e63586
Number of pages	27
Journal	eLife
Volume	10
Early online date	11 Feb 2021
DOIs	https://doi.org/10.7554/eLife.63586
Publication status	Published - 18 Mar 2021

Bibliographical note

Publisher Copyright:
© 2021, Macpherson et al.

Keywords

Allosteric Regulation/drug effects
Animals
Cattle
Complement C5/antagonists & inhibitors
Drug Discovery
Molecular Docking Simulation
Peptides/chemistry
Protein Conformation/drug effects

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Macpherson, A., Laabei, M., Ahdash, Z., Graewert, M. A., Birtley, J. R., Schulze, M.-S. 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. (2021). The allosteric modulation of complement C5 by knob domain peptides. eLife, 10, Article e63586. https://doi.org/10.7554/eLife.63586

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title = "The allosteric modulation of complement C5 by knob domain peptides",

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 {\AA} 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.",

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author = "Alex Macpherson and Maisem Laabei and Zainab Ahdash and Graewert, {Melissa A} and Birtley, {James R} and Schulze, {Monika-Sarah Ed} and Susan Crennell and Robinson, {Sarah A} and Ben Holmes and Vladas Oleinikovas and Nilsson, {Per H} and James Snowden and Victoria Ellis and Mollnes, {Tom Eirik} and Deane, {Charlotte M} and Dmitri Svergun and Lawson, {Alastair Dg} and {van den Elsen}, {Jean Mh}",

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Macpherson, A, Laabei, M, Ahdash, Z, Graewert, MA, Birtley, JR, Schulze, M-SE, Crennell, S, Robinson, SA, Holmes, B, Oleinikovas, V, Nilsson, PH, Snowden, J, Ellis, V, Mollnes, TE, Deane, CM, Svergun, D, Lawson, AD & van den Elsen, JM 2021, 'The allosteric modulation of complement C5 by knob domain peptides', eLife, vol. 10, e63586. https://doi.org/10.7554/eLife.63586

TY - JOUR

T1 - The allosteric modulation of complement C5 by knob domain peptides

AU - Macpherson, Alex

AU - Laabei, Maisem

AU - Ahdash, Zainab

AU - Graewert, Melissa A

AU - Birtley, James R

AU - Schulze, Monika-Sarah Ed

AU - Crennell, Susan

AU - Robinson, Sarah A

AU - Holmes, Ben

AU - Oleinikovas, Vladas

AU - Nilsson, Per H

AU - Snowden, James

AU - Ellis, Victoria

AU - Mollnes, Tom Eirik

AU - Deane, Charlotte M

AU - Svergun, Dmitri

AU - Lawson, Alastair Dg

AU - van den Elsen, Jean Mh

PY - 2021/3/18

Y1 - 2021/3/18

N2 - 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.

AB - 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.

KW - Allosteric Regulation/drug effects

KW - Animals

KW - Cattle

KW - Complement C5/antagonists & inhibitors

KW - Drug Discovery

KW - Molecular Docking Simulation

KW - Peptides/chemistry

KW - Protein Conformation/drug effects

U2 - 10.7554/eLife.63586

DO - 10.7554/eLife.63586

M3 - Article (Academic Journal)

C2 - 33570492

SN - 2050-084X

VL - 10

JO - eLife

JF - eLife

M1 - e63586

ER -

The allosteric modulation of complement C5 by knob domain peptides

Abstract

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Keywords

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