The D2
code
analysis of a large collection of crystal structures
of human
immunodeficiency virus type 1 protease (HIV-1 PR) variants
can provide a new perspective to the problem of drug
resistance and lead to new ideas on designing more
efficient drugs.
The D2 code
analysis can be also useful in rational drug design. For
instance, analysis of the distribution of D2-variable
regions may lead to a more detailed description of the mechanism of multi-drug resistance due
to non-active site mutations. As an example, let's
consider mutations in HIV-1
protease
which produce resistance to HIV-1 protease inhibitors, one of the major
anti-HIV-1 drug targets, in the therapy of HIV-1 infection [1].
Because
of the short life cycle and the high mutation rate of HIV-1, every
mutation of HIV-1 protease is created thousands of time each day in
each patient [2]. As a result, HIV-1 protease exists within a patient
as a mixture of genetically related but distinguishable variants often
referred to as a ``swarm''
or ``quasi-species'' [3].
Drug-resistant HIV-1 strains are then developed under the selective
pressure of protease inhibitor therapy.
More than 60 mutations are currently associated with protease
inhibitor resistance [4], which could be classified
as active site
or non-active site
mutations depending on their location
within the protease molecule. The mechanism of resistance due to
non-active site mutations is not immediately apparent unlike the case
of active site mutations, and extensive studies have been made on this
topic ([5]--[9]), although the detailed
mechanisms of drug resistance are yet to be clarified.
In the following, superposition of molecules and their Z-scores
and RMSDs are computed by the DaliLite server
([10]--[11]).
(0) About the structure of HIV-1 PR
HIV-1 PR is a homodimeric
molecule, consisted of two identical 99-residue polypeptide chains.
HIV-1 PR is a C2-symmetric molecule, with a twofold axis transversing
the active site (residues Asp25, Thr26, and Gly27).
(1) X-ray crystal structures of HIV-1 PR variants from
the PDB database
- Crystal structures of space group P 61
- Crystal
structures of space group P 21
21 2
- HIV-1 PR complexed with the FDA approved drugs
- HIV-1 PR complexed with peptidomimetic inhibitors
- HIV-1 PR complexed with non-peptide based inhibitors
- Crystal
structures of space group P 21
21 21
- HIV-1 PR
complexed with the FDA approved drugs
- HIV-1 PR
complexed with peptidomimetic inhibitors
- HIV-1 PR
complexed with non-peptide based inhibitors
- Crystal
structures of the other space groups
- HIV-1 PR
complexed with the FDA approved drugs
- HIV-1 PR
complexed with peptidomimetic inhibitors
- HIV-1 PR
complexed with non-peptide based inhibitors
- Deviation from
C2-symmetry upon ligand-binding
- Difference between the D2 codes
of chain A and chain B
*) FDA:= U.S. Food and Drug Administration.
(2) NMR structures
(solution structures)
of HIV-1 PR variants
References
- Wlodawer A, Vondrasek J. Inhibitors of HIV-1 protease: a
major success
of structure-assisted drug design. Annu Rev Biophys Biomol Struct
1998;27:249-84.
- Shafera RW, Rheea S-Y, Pillayb D, Millerc V, Sandstromd P,
Schapiroa JM, Kuritzkese DR, Bennettf D. HIV-1protease and reverse
transcriptase mutations for drug resistance surveillance. AIDS
2007;21:215-223.
- Rhee SY, Gonzales MJ, Kantor R, Betts BJ, Ravela J, Shafer
RW. Human immunodeficiency virus reverse transcriptase and protease
sequence database. Nucleic Acids Res 2003;31:298-303.
- Shafer RW, Schapiro JM. HIV-1 drug resistance mutations: an
updated framework for the second decade of HAART, AIDS Rev.
2008;10:67-84.
- Piana S, Carloni P, Rothlisberger U. Drug resistance in
HIV-1 protease: flexibility-assisted mechanism of compensatory
mutations. Protein Sci 2002;11: 2393-2402.
- Zoete V, Michielin O, Karplus M. Relation between sequence
and structure of HIV-1 protease inhibitor complexes: a model system for
the analysis of protein flexibility. J Mol Biol 2002;315:21-52.
- Ohtaka H, Schon A, Freire E. Multidrug resistance to HIV-1
protease inhibition requires cooperative coupling between distal
mutations. Biochemistry 2003;42:13659-66.
- Prabu-Jeyabalan M, Nalivaika EA, King NM, Schiffer CA.
Viability of a drug-resistant human immunodeficiency virus type 1
protease variant: structural insights for better antiviral therapy.
Virol 2003;77:1306-15.
- Ode H, Neya S, Hata M, Sugiura W, Hoshino T. Computational
simulations of HIV-1 proteases-multi-drug resistance due to nonactive
site mutation L90M. J Am Chem Soc 2006;128:7887 -7895.
- Holm, L. and Park J. (2000) DaliLite workbench for
protein structure comparison. Bioinformatics,
16:566-567.
- The pairwise DaliLite
server : http://www.ebi.ac.uk/DaliLite/