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2.3.2 TR/pMHC
The analysis of the pairwise contacts that occur at the TR/MHC and TR/peptide inter-
faces was carried out using the IMGT unique numbering for V-DOMAINs (Lefranc
et al. 2003b) for the TR, and the IMGT unique numbering for G-DOMAINs for the
MHC (Lefranc et al. 2005b). Table 3 shows the interactions of the TR V-ALPHA and
TR V-BETA with MHC-I and the peptide, in nine TR/pMHC-I 3D structures. Table 4
shows the interactions of the TR V-ALPHA and TR V-BETA with MHC-II and the
peptide, in two TR/pMHC-II 3D structures. The results show that positions implicated
in the binding are well conserved but not the pairwise interactions. The MHC contact
positions belong to the G-DOMAIN helices. The TR positions that are involved in the
contacts belong mostly to the CDR-IMGT and to anchor positions (shown by squares
in Fig. 2). The FR-IMGT positions involved in the contacts are positions 84 and 84A
that are located at the DE turn (designated as “hypervariable 4” or HV4). The contact
analysis confirms that the V-ALPHA CDR2-IMGT seats on top of the G-ALPHA2
(MHC-I) or G-BETA (MHC-II) helices and that the V-BETA CDR2-IMGT seats on
top of the G-ALPHA1 (MHC-I) or G-ALPHA (MHC-II) helices (Tables 3 and 4). This
agrees with data (Sim et al. 1996) which showed that most of the TR/MHC specificity
comes from the CDR1 and CDR2 because mutations in these CDRs are able to change
specificity between MHC-I and MHC-II. V-ALPHA and V-BETA CDR3-IMGT usu-
ally follow the same G-DOMAIN contact preference as the CDR2-IMGT but they can
also have contacts with the other G-DOMAINs. For example, in the 1oga 3D structure,
position 66 of G-ALPHA2 is contacted by the V-ALPHA CDR3-IMGT but also by the
V-BETA CDR3-IMGT.
The diagonal orientation of the TR/pMHC complex puts the TR in a globally con-
served position for a peptide “read-out” (Buslepp et al. 2003). V-ALPHA is on top of
the peptide N terminus while V-BETA is on top of the peptide C terminus. TR posi-
tions implicated in the peptide recognition are in CDR3-IMGT and generally to a lesser
extent in V-ALPHA CDR1-IMGT (Tables 3 and 4). Nearly every 3D structure shows
different CDR3 conformations and binding mode. In the JM22/peptide/HLA-A
complex (1oga) (Stewart-Jones et al. 2003), the V-BETA CDR3-IMGT extensively
contacts the peptide and G-ALPHA2 through hydrogen bonds (Table 3), by inserting
itself between the peptide and the G-ALPHA2. In contrast, the 2C/peptide/H2-
K1complex (1jtr) (Degano et al. 2000) has comparatively fewer contacts between the
V-BETA CDR3-IMGT and the peptide and the MHC; however the V-BETA CDR1-
IMGT has more contacts and hydrogen bonds with the peptide and G-ALPHA2.
The TR LC13 and 2C were crystallized both alone and in complex with a pMHC.
The structural superimposition of both V-DOMAIN scaffold
α
carbons reveals large
movements of the CDR3 and of the CDR1, respectively. The V-ALPHA domains of
LC13, in the 1mi5 and 1kgc 3D structures, have 3.5 Å root mean square (RMS) between
their CDR3. The V-ALPHA domains of 2C, in the 2ckb and 1tcr 3D structures, have 2.3
Å RMS between their CDR1. The TR A6 was crystallized in complex with the same
MHC but with different peptides. In these structures, the V-BETA CDR3 adopt different
conformations to adapt to the different peptides (Rudolph, Luz, and Wilson 2002). The
CDR3 conformational change does not increase the binding surface but gives a better
shape complementarity to the interface (Lawrence and Colman 1993).
