Academic Projects:
5. Structural studies on proteins of M. tuberculosis
(Collaborators: Seyed E. Hasnain, Ranjan Sen)
One of the long
standing interests of our laboratory has been on addressing structure-function properties
of a wide variety of proteins derived from M.
tuberculosis. We have limited our focus on M. tuberculosis for the reason that it affects most part of the
poor world, and that understanding of the disease has remained inadequate
despite enhanced scientific efforts. Our
attempt is to determine three-dimensional structures of these proteins, and
correlate the properties to the bacterium, wherever possible. During these studies our laboratory has also
participated in the international Tuberculosis Structural Genomics Consortium,
currently coordinated by Prof. Jim Sacchettini, Texax A& M University.
Our early focus has
been on the structures of Hsp10 (GroES) and Hsp65 (GroEL-2). From the structures we were able to propose
that the GroES possesses divalent cation binding site, where it might have
relevance in understanding Pott’s disease.
We were also able to determine the structure of GroEL-2 in its dimeric
form.
We have also been
interested in the structure-function properties of redox proteins. Our structure of thioredoxin reductase showed
that it possesses large dynamic behavior.
We were able to study the dynamic properties though the analysis of TLS
parameters derived from crystallographic refinement, and were able to show
excellent correlation with Normal Mode Analysis.
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One
of the structures determined in our laboratory was that of the chorismate
mutase. This enzyme is a key enzyme in
the aromatic amino acid biosynthesis and is considered to be an attractive
drug target. The enzyme is different
in M. tuberculosis compared to
other prokaryotes. Our structure reveals that there might have been an internal
gene duplication in the M. tuberculosis
chorismate mutase gene. It is also
believed to be allosterically regulated.
Our structure provides insight into the allosteric regulation by its
ligand, tryptophan. |
Structure of M.
tuberculosis Chorismate mutase dimer, with the bound allosteric ligand-
Trp. |
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One of our recent structures is
that of the M. tuberculosis YefM
antitoxin. This was believed to be an
intrinsically disordered protein. However, we were able to crystallize it
fortuitously. Analysis of many
conserved YefM sequences and our structure together suggests that it is
unlikely to be intrinsically disordered.
Moreover, our structure also provides insights into its disassociation
from the YoeB toxin at low pH. |
Structure of the tetrameric
antitoxin, where the dimers are formed through a conserved hydrophobic core. The two dimers in a tetramer are associated
weakly, and provides insight into the disassociation of toxin: antitoxin
complex. |
The monomer of YefM is formed of
three distinct regions, the N-terminal head domain that is involved in
dimerization, central helix and the C-terminal helices that are involved in
tetramerization. |
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Crystallization
and preliminary X-ray crystallographic studies of Mycobacterium tuberculosis
CRP/FNR family transcription regulator (PDF)
Mohd. Akif, Y. Akhter,
S. E. Hasnain and S. C. Mande
Acta crystallogr. (2006) F62, 873-875.
·
The 2.15Å crystal
structure of M. tuberculosis chorismate mutase reveals unexpected gene
duplication, and suggests a role in host-pathogen interactions (PDF)
R. Qamra, P. Prakash, B. Aruna, S.
E. Hasnain and S. C. Mande
Biochemistry (2006) 45,
6997- 7005.
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Cation mediated
interplay of loops in Mycobacterium tuberculosis Chaperonin-10 (PDF)
S. Vijaykrishnan, R. Qamra, C.
Verma, R. Sen and S. C. Mande
J. Biomolec. Struct. Dyn. (2006) 23, 365- 376.
·
Conformational
flexibility of M. tuberculosis Thioredoxin reductase: Crystal Structure
and Normal Mode Analysis (PDF)
Mohd. Akif, K. Suhre, C. Verma and S.
C. Mande
Acta crystallogr. (2005) D61, 1603- 1611.
·
Crystallization and preliminary X-ray crystallographic studies of Mycobacterium
tuberculosis chorismate mutase (PDF)
R. Qamra, P. Prakash, B. Aruna, S. E. Hasnain and S. C. Mande
Acta crystallogr. (2005) F61, 473-475.
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Crystal Structure of the 65 kDa Heat Shock Protein, Chaperonin 60.2 of Mycobacterium tuberculosis (PDF)
R. Qamra and S. C. Mande
J. Bacteriol. (2004) 186, 8105-8113.
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Expression,
purification, crystallization and preliminary X-ray crystallographic studies of
Mycobacterium tuberculosis thioredoxin reductase (PDF)
Mohd. Akif, R. Chauhan and S. C.
Mande
Acta Crystallogr D (2004) 60, 777-779
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Structure of Mycobacterium
tuberculosis chaperonin-10 at 3.5 Å resolution (PDF)
B. Taneja and S. C.
Mande
Acta Crystallogr (2002)
D58, 260-266.
·
Three- dimensional
structure of Mycobacterium tuberculosis chaperonin-10 reveals a partially
stable conformation of its mobile loop (PDF)
B. Taneja and S. C.
Mande
Curr. Sci. (2001) 81, 87- 91.
·
Metal ions
modulate the plastic nature of Mycobacterium tuberculosis chaperonin-10
(PDF)
B. Taneja and S. C.
Mande
Prot. Eng.
(2001) 14, 391- 395.
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