PMID- 29247053
OWN - NLM
STAT- MEDLINE
DCOM- 20180709
LR  - 20220129
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 115
IP  - 1
DP  - 2018 Jan 2
TI  - Affimer proteins inhibit immune complex binding to FcgammaRIIIa with high specificity 
      through competitive and allosteric modes of action.
PG  - E72-E81
LID - 10.1073/pnas.1707856115 [doi]
AB  - Protein-protein interactions are essential for the control of cellular functions 
      and are critical for regulation of the immune system. One example is the binding 
      of Fc regions of IgG to the Fc gamma receptors (FcgammaRs). High sequence identity 
      (98%) between the genes encoding FcgammaRIIIa (expressed on macrophages and natural 
      killer cells) and FcgammaRIIIb (expressed on neutrophils) has prevented the 
      development of monospecific agents against these therapeutic targets. We now 
      report the identification of FcgammaRIIIa-specific artificial binding proteins called 
      "Affimer" that block IgG binding and abrogate FcgammaRIIIa-mediated downstream 
      effector functions in macrophages, namely TNF release and phagocytosis. Cocrystal 
      structures and molecular dynamics simulations have revealed the structural basis 
      of this specificity for two Affimer proteins: One binds directly to the Fc 
      binding site, whereas the other acts allosterically.
FAU - Robinson, James I
AU  - Robinson JI
AD  - Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, 
      University of Leeds, Leeds LS9 7TF, United Kingdom.
AD  - National Institute of Health Research-Leeds Biomedical Research Centre, Chapel 
      Allerton Hospital, Leeds LS7 4SA, United Kingdom.
FAU - Baxter, Euan W
AU  - Baxter EW
AD  - Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, 
      University of Leeds, Leeds LS9 7TF, United Kingdom.
AD  - National Institute of Health Research-Leeds Biomedical Research Centre, Chapel 
      Allerton Hospital, Leeds LS7 4SA, United Kingdom.
FAU - Owen, Robin L
AU  - Owen RL
AD  - Diamond Light Source, Didcot OX11 0DE, United Kingdom.
FAU - Thomsen, Maren
AU  - Thomsen M
AD  - Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds 
      LS2 9JT, United Kingdom.
FAU - Tomlinson, Darren C
AU  - Tomlinson DC
AUID- ORCID: 0000-0003-4134-7484
AD  - Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds 
      LS2 9JT, United Kingdom.
AD  - BioScreening Technology Group, School of Molecular and Cellular Biology, 
      University of Leeds, Leeds LS2 9JT, United Kingdom.
FAU - Waterhouse, Mark P
AU  - Waterhouse MP
AD  - Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, 
      University of Leeds, Leeds LS9 7TF, United Kingdom.
AD  - National Institute of Health Research-Leeds Biomedical Research Centre, Chapel 
      Allerton Hospital, Leeds LS7 4SA, United Kingdom.
FAU - Win, Stephanie J
AU  - Win SJ
AD  - Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, 
      University of Leeds, Leeds LS9 7TF, United Kingdom.
AD  - National Institute of Health Research-Leeds Biomedical Research Centre, Chapel 
      Allerton Hospital, Leeds LS7 4SA, United Kingdom.
FAU - Nettleship, Joanne E
AU  - Nettleship JE
AD  - Oxford Protein Production Facility-United Kingdom Research Complex at Harwell, 
      Rutherford Appleton Laboratory, Oxford OX11 0FA, United Kingdom.
AD  - Division of Structural Biology, Wellcome Trust Centre for Genomic Medicine, 
      Nuffield Department of Medicine, Oxford University, Oxford OX3 7BN, United 
      Kingdom.
FAU - Tiede, Christian
AU  - Tiede C
AD  - BioScreening Technology Group, School of Molecular and Cellular Biology, 
      University of Leeds, Leeds LS2 9JT, United Kingdom.
FAU - Foster, Richard J
AU  - Foster RJ
AD  - Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds 
      LS2 9JT, United Kingdom.
AD  - School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom.
FAU - Owens, Raymond J
AU  - Owens RJ
AD  - Oxford Protein Production Facility-United Kingdom Research Complex at Harwell, 
      Rutherford Appleton Laboratory, Oxford OX11 0FA, United Kingdom.
AD  - Division of Structural Biology, Wellcome Trust Centre for Genomic Medicine, 
      Nuffield Department of Medicine, Oxford University, Oxford OX3 7BN, United 
      Kingdom.
FAU - Fishwick, Colin W G
AU  - Fishwick CWG
AD  - Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds 
      LS2 9JT, United Kingdom.
AD  - School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom.
FAU - Harris, Sarah A
AU  - Harris SA
AD  - Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds 
      LS2 9JT, United Kingdom.
AD  - School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, United 
      Kingdom.
FAU - Goldman, Adrian
AU  - Goldman A
AD  - BioScreening Technology Group, School of Molecular and Cellular Biology, 
      University of Leeds, Leeds LS2 9JT, United Kingdom.
AD  - Faculty of Biological and Environmental Sciences, University of Helsinki, 
      FIN-0014 Helsinki, Finland.
FAU - McPherson, Michael J
AU  - McPherson MJ
AD  - Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds 
      LS2 9JT, United Kingdom; M.J.McPherson@leeds.ac.uk A.W.Morgan@leeds.ac.uk.
AD  - BioScreening Technology Group, School of Molecular and Cellular Biology, 
      University of Leeds, Leeds LS2 9JT, United Kingdom.
FAU - Morgan, Ann W
AU  - Morgan AW
AUID- ORCID: 0000-0003-1109-624X
AD  - Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, 
      University of Leeds, Leeds LS9 7TF, United Kingdom; M.J.McPherson@leeds.ac.uk 
      A.W.Morgan@leeds.ac.uk.
AD  - National Institute of Health Research-Leeds Biomedical Research Centre, Chapel 
      Allerton Hospital, Leeds LS7 4SA, United Kingdom.
LA  - eng
SI  - PDB/5ML9
SI  - PDB/5MN2
GR  - MR/K015346/1/MRC_/Medical Research Council/United Kingdom
GR  - DH_/Department of Health/United Kingdom
GR  - BB/M021610/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - MR/K018779/1/MRC_/Medical Research Council/United Kingdom
GR  - 094232/Z/10/Z/WT_/Wellcome Trust/United Kingdom
GR  - 19764/ARC_/Arthritis Research UK/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
GR  - MC_PC_14109/MRC_/Medical Research Council/United Kingdom
GR  - 19764/VAC_/Versus Arthritis/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171215
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antigen-Antibody Complex)
RN  - 0 (FCGR3A protein, human)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Receptors, IgG)
SB  - IM
MH  - Allosteric Regulation
MH  - Antigen-Antibody Complex/*chemistry/immunology
MH  - Humans
MH  - Immunoglobulin G/*chemistry/immunology
MH  - *Molecular Dynamics Simulation
MH  - Receptors, IgG/*chemistry/immunology
PMC - PMC5776790
OTO - NOTNLM
OT  - Affimer
OT  - Fc gamma receptor IIIa
OT  - allosteric
OT  - competitive
OT  - specific inhibitor
COIS- Conflict of interest statement: The University of Leeds has filed a patent 
      application on Adhiron (referred to here as Affimer protein) that is licensed to 
      Avacta Life Sciences Ltd.
EDAT- 2017/12/17 06:00
MHDA- 2018/07/10 06:00
PMCR- 2018/07/02
CRDT- 2017/12/17 06:00
PHST- 2017/12/17 06:00 [pubmed]
PHST- 2018/07/10 06:00 [medline]
PHST- 2017/12/17 06:00 [entrez]
PHST- 2018/07/02 00:00 [pmc-release]
AID - 1707856115 [pii]
AID - 201707856 [pii]
AID - 10.1073/pnas.1707856115 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2018 Jan 2;115(1):E72-E81. doi: 
      10.1073/pnas.1707856115. Epub 2017 Dec 15.