TY - JOUR
T1 - The origin of CDR H3 structural diversity
AU - Weitzner, Brian D.
AU - Dunbrack, Roland L.
AU - Gray, Jeffrey J.
N1 - Funding Information:
The authors would like to acknowledge Qifang Xu for providing alignments of LAT+kink matches to Pfam HMMs; Matthew J. O'Meara for assistance with the Rosetta features analysis framework; Christopher R. Shaffer, Andrew P. Leaver-Fay, and Daisuke Kuroda for helpful discussions; and Danielle C. Hein and Robert Schleif for providing critical feedback on the manuscript. This work was supported by National Institutes of Health Grants R01 GM084453 to R.L.D. and R01 GM078221 to J.J.G.
Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/2/3
Y1 - 2015/2/3
N2 - Antibody complementarity determining region (CDR) H3 loops are critical for adaptive immunological functions. Although the other five CDR loops adopt predictable canonical structures, H3 conformations have proven unclassifiable, other than an unusual C-terminal "kink" present in most antibodies. To determine why the majority of H3 loops are kinked and to learn whether non-antibody proteins have loop structures similar to those of H3, we searched a set of 15,679 high-quality non-antibody structures for regions geometrically similar to the residues immediately surrounding the loop. By incorporating the kink into our search, we identified 1,030 H3-like loops from 632 protein families. Some protein families, including PDZ domains, appear to use the identified region for recognition and binding. Our results suggest that the kink is conserved in the immunoglobulin heavy chain fold because it disrupts the β-strand pairing at the base of the loop. Thus, the kink is a critical driver of the observed structural diversity in CDR H3.
AB - Antibody complementarity determining region (CDR) H3 loops are critical for adaptive immunological functions. Although the other five CDR loops adopt predictable canonical structures, H3 conformations have proven unclassifiable, other than an unusual C-terminal "kink" present in most antibodies. To determine why the majority of H3 loops are kinked and to learn whether non-antibody proteins have loop structures similar to those of H3, we searched a set of 15,679 high-quality non-antibody structures for regions geometrically similar to the residues immediately surrounding the loop. By incorporating the kink into our search, we identified 1,030 H3-like loops from 632 protein families. Some protein families, including PDZ domains, appear to use the identified region for recognition and binding. Our results suggest that the kink is conserved in the immunoglobulin heavy chain fold because it disrupts the β-strand pairing at the base of the loop. Thus, the kink is a critical driver of the observed structural diversity in CDR H3.
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U2 - 10.1016/j.str.2014.11.010
DO - 10.1016/j.str.2014.11.010
M3 - Article
C2 - 25579815
AN - SCOPUS:84930190530
SN - 0969-2126
VL - 23
SP - 302
EP - 311
JO - Structure
JF - Structure
IS - 2
ER -