selected as template structure for modeling. However, in cross-taxonomy (with
eukaryote) 1LWD [65], same target sequence had higher sequence identity (Table 2)
than E. coli. Both crystal structures (3ICD and 1LWD) have same Rossmann fold and
a common dinucleotide-binding domain [64, 65].
In such case, where target structure from the same taxonomy is available and
fulfills the most homology modeling criteria, it is not always true that model
structure will also provide functional explanation. Model developed using E. coli is
shown in Fig. 2a (dark gray color) with E. coli crystal structure (green color). Both
structures are superimposed well with RMSD 4.68 Å. However, model structure
(white color) developed using Sus scrofa (orange color) as template superimposes
with crystal structure with RMSD of 0.57 Å (Fig. 2c). Both models are validated
using PROCHECK [55], and more than 85% residues are found under
Ramachandran region. So, both models follow homology criterion and passed by
the structure validation tools.
In 2013, Quartararo et al. published the crystal structure of Mtb ICD dimer
complex with NADPH. This structure is then used to understand the closeness of
modeled structure of Mtb ICD with both E. coli and Sus scrofa. Superimposition of
Mtb with E. coli and Sus scrofa is shown in Fig. 2b, d, respectively. Although all
three have same folds, Sus scrofa is more close toward Mtb than E. coli. E. coli
structure has 6.4 Å RMSD with Mtb, and major differences occurred in the
beta-hairpin loop region where E. coli structure has helical element than
beta-structure element. This region of dissimilarity known as clasp region between
inter-subunit interface [64] plays important functional role during phosphorylation
[61].
So, from this case study, it is very clear that one template cannot guarantee about
the functional state of the homology model, so different templates may be used to
develop appropriate functional model, as mentioned in comparative modeling
review [53]. Key to the selection of the model is always to be associated with the
Table 2 Comparison of the crystal structure of Mtb
a with selected (template) prokaryote and
eukaryote crystal structures
ICDH
Mtb
Sus scrofa
E. coli
Sequence length
409
413
416
Template PDB ID
4HCX [66]
1LWD [65]
3ICD [64]
Year of publication
2013
2002
1989
Template structure resolution (Å)
2.18
1.85
2.5
R free
0.262
1.85 Å
NA
R work
0.205
0.210
0.180
Ramachandran outliers (%)
1.8
0.2
0.5
Sequence Identity with respect to Mtb ICDH
(UniProt ID: P9WKL1) (%)
100
65.2
23.6
Sequence Similarity with respect to Mtb ICDH
(UniProt ID: P9WKL1) (%)
100
79.2
35.7
a Earlier modeled because structure was not available till 2013
120
S. K. Panday and I. Ghosh
eukaryote) 1LWD [65], same target sequence had higher sequence identity (Table 2)
than E. coli. Both crystal structures (3ICD and 1LWD) have same Rossmann fold and
a common dinucleotide-binding domain [64, 65].
In such case, where target structure from the same taxonomy is available and
fulfills the most homology modeling criteria, it is not always true that model
structure will also provide functional explanation. Model developed using E. coli is
shown in Fig. 2a (dark gray color) with E. coli crystal structure (green color). Both
structures are superimposed well with RMSD 4.68 Å. However, model structure
(white color) developed using Sus scrofa (orange color) as template superimposes
with crystal structure with RMSD of 0.57 Å (Fig. 2c). Both models are validated
using PROCHECK [55], and more than 85% residues are found under
Ramachandran region. So, both models follow homology criterion and passed by
the structure validation tools.
In 2013, Quartararo et al. published the crystal structure of Mtb ICD dimer
complex with NADPH. This structure is then used to understand the closeness of
modeled structure of Mtb ICD with both E. coli and Sus scrofa. Superimposition of
Mtb with E. coli and Sus scrofa is shown in Fig. 2b, d, respectively. Although all
three have same folds, Sus scrofa is more close toward Mtb than E. coli. E. coli
structure has 6.4 Å RMSD with Mtb, and major differences occurred in the
beta-hairpin loop region where E. coli structure has helical element than
beta-structure element. This region of dissimilarity known as clasp region between
inter-subunit interface [64] plays important functional role during phosphorylation
[61].
So, from this case study, it is very clear that one template cannot guarantee about
the functional state of the homology model, so different templates may be used to
develop appropriate functional model, as mentioned in comparative modeling
review [53]. Key to the selection of the model is always to be associated with the
Table 2 Comparison of the crystal structure of Mtb
a with selected (template) prokaryote and
eukaryote crystal structures
ICDH
Mtb
Sus scrofa
E. coli
Sequence length
409
413
416
Template PDB ID
4HCX [66]
1LWD [65]
3ICD [64]
Year of publication
2013
2002
1989
Template structure resolution (Å)
2.18
1.85
2.5
R free
0.262
1.85 Å
NA
R work
0.205
0.210
0.180
Ramachandran outliers (%)
1.8
0.2
0.5
Sequence Identity with respect to Mtb ICDH
(UniProt ID: P9WKL1) (%)
100
65.2
23.6
Sequence Similarity with respect to Mtb ICDH
(UniProt ID: P9WKL1) (%)
100
79.2
35.7
a Earlier modeled because structure was not available till 2013
120
S. K. Panday and I. Ghosh