TY - JOUR
T1 - Role of Non-local Interactions between CDR Loops in Binding Affinity of MR78 Antibody to Marburg Virus Glycoprotein
AU - Sangha, Amandeep K.
AU - Dong, Jinhui
AU - Williamson, Lauren
AU - Hashiguchi, Takao
AU - Saphire, Erica Ollmann
AU - Crowe, James E.
AU - Meiler, Jens
N1 - Funding Information:
A.K.S. is grateful to Dr. Frank DiMaio for technical discussions on the Phenix.Rosetta refinement technique, and to Jessica Ann Finn, Alexander Sevy, and Alberto Cisneros for helpful discussions. The work was supported through NIH grants R21 AI121799 (J.M.), U19 AI117905 (J.E.C. and J.M.), U19 AI109711 (J.E.C.), and DTRA grant HDTRA1-13-1-0034 (J.E.C.). Work in the Saphire laboratory is supported through NIH U19AI1097652 and R01 AI089498. This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract number DE-AC02-06CH11357. Updated coordinates for the MR78-MARV GP complex, including additional insights from separate work (L.B. King et al., unpublished data), have been deposited in the PDB under PDB: 5UQY.
Funding Information:
A.K.S. is grateful to Dr. Frank DiMaio for technical discussions on the Phenix.Rosetta refinement technique, and to Jessica Ann Finn, Alexander Sevy, and Alberto Cisneros for helpful discussions. The work was supported through NIH grants R21 AI121799 (J.M.), U19 AI117905 (J.E.C. and J.M.), U19 AI109711 (J.E.C.), and DTRA grant HDTRA1-13-1-0034 (J.E.C.). Work in the Saphire laboratory is supported through NIH U19AI1097652 and R01 AI089498 . This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract number DE-AC02-06CH11357. Updated coordinates for the MR78-MARV GP complex, including additional insights from separate work (L.B. King et al., unpublished data), have been deposited in the PDB under PDB: 5UQY .
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/12/5
Y1 - 2017/12/5
N2 - An atomic-detail model of the Marburg virus glycoprotein in complex with a neutralizing human monoclonal antibody designated MR78 was constructed using Phenix.Rosetta starting from a 3.6Å crystallographic density map. The Asp at T6 in the HCDR3's bulged torso cannot form the canonical salt bridge as position T2 lacks an Arg or Lys residue. It instead engages in a hydrogen bond interaction with a Tyr contributed by the HCDR1 loop. This inter-CDR loop interaction stabilizes the bulged conformation needed for binding to the viral glycoprotein: a Tyr to Phe mutant displays a binding affinity reduced by a factor of at least 10. We found that 5% of a database of 465 million human antibody sequences has the same residues at T2 and T6 positions in HCDR3 and Tyr in HCDR1 that could potentially form this Asp-Tyr interaction, and that this interaction might contribute to a non-canonical bulged torso conformation. Sangha et al. have discovered that the conformation of the human antibody MR78 HCDR3 loop that binds to Marburg virus glycoprotein is stabilized by a non-local hydrogen bond between an Asp at T6 position of HCDR3 and a Tyr in HCDR1.
AB - An atomic-detail model of the Marburg virus glycoprotein in complex with a neutralizing human monoclonal antibody designated MR78 was constructed using Phenix.Rosetta starting from a 3.6Å crystallographic density map. The Asp at T6 in the HCDR3's bulged torso cannot form the canonical salt bridge as position T2 lacks an Arg or Lys residue. It instead engages in a hydrogen bond interaction with a Tyr contributed by the HCDR1 loop. This inter-CDR loop interaction stabilizes the bulged conformation needed for binding to the viral glycoprotein: a Tyr to Phe mutant displays a binding affinity reduced by a factor of at least 10. We found that 5% of a database of 465 million human antibody sequences has the same residues at T2 and T6 positions in HCDR3 and Tyr in HCDR1 that could potentially form this Asp-Tyr interaction, and that this interaction might contribute to a non-canonical bulged torso conformation. Sangha et al. have discovered that the conformation of the human antibody MR78 HCDR3 loop that binds to Marburg virus glycoprotein is stabilized by a non-local hydrogen bond between an Asp at T6 position of HCDR3 and a Tyr in HCDR1.
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U2 - 10.1016/j.str.2017.10.005
DO - 10.1016/j.str.2017.10.005
M3 - Article
C2 - 29153506
AN - SCOPUS:85034451888
VL - 25
SP - 1820-1828.e2
JO - Structure with Folding & design
JF - Structure with Folding & design
SN - 0969-2126
IS - 12
ER -