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Journal Club 2011-05-24 Protein Conformational Database
Transcript of Journal Club 2011-05-24 Protein Conformational Database
2011-05-24 Tobias Sikosek look at available protein structures in the PDB database look for proteins with more than one structure How do we typically think about protein structures? ordered structured disordered alpha helix beta sheet protein folding random coil structure induced by binding many interaction partners DNA binding transcription factors protein-protein interaction example: ubiquitin something in between conformational ensemble native state ensemble geared towards single native state more than one native state example: Mad2 idea: normal variation between repeated crystallography experiments under same conditions: 0.1 to 0.4 Angstrom binding of ligands
change in oligomeric state (protein complexes)
temperature and pH
mutations sources of conformational variation each protein cross-linked to gene ontology (GO)
Enzyme commission (EC)
structural classification (CATH)
NCBI taxonomy ID
Catalytic Site Atlas
InterPro RMSDmax :
if more than two structures known for the same protein RMSD (root mean square deviation):
measure of the average distance between the atoms (usually the backbone atoms) of superimposed proteins. crystallographic conditions that effect structure how do we measure conformational diversity?
nuclear magnetic resonance (NMR)
molecular dynamics simulations
separate X-ray crystallography experiments future developments:
sequence alignments for each protein
expand to close homologues conservation of positions
evolutionary rates proteins with high (but less than 100%) sequence identity with different structures actually, this has been attempted already: redundant X-ray structure depositions dominate PDB
(~50000 deposition represent ~15000 proteins, i.e. ~4x redundancy)
most large-scale analyses of PDB performed on non-redundant dataset 12406 clusters (100% seq id)
7206 clusters with >1 structure
3720 clusters with exactly 2 structures (most convenient for comparison)
(~600 clusters with >10 entries)
most structures of length 100-400 res. the data set: Lig = structure with ligand bound
Nat = structure without ligand (native)
binding of ligand makes structure more rigid,
--> less conformational diversity ? contrary to expectation:
RMSD does NOT increase with protein length! shallow tree:
protein with small conformation changes deep tree:
protein with large
conformation changes RMSD RMSD "cut" tree at certain RMSD and
obtain number of branaches
(= conformations) No. of branches
in tree RMSD cutoff in tree No. of branches
in tree what is the origin of conformational diversity?
is entire protein chain dynamic?
or are there rigid parts moving against each other?
--> use sliding window of structure comparison transhydroxylase diphtheria toxin calmodulin apolipoprotein A fragment of apolipoprotein A diphtheria toxin transhydroxylase calmodulin largest conformational change (23.7 Angtrom RMSD):
Src kinase (2 domains with hinge) (large and rigid) (many conformational states) (highly mobile; largest number of conformational states in study) sliding window of 25 residues (3 pairwise comparisons) rigid region hinge region every protein has a different peak:
characteristic balance between rigidity and mobility pre-liminary results:
enrichment of keywords "motor" and "transduction"
for proteins with many conformational states Conclusions: only 25% of high-resolution X-ray structures have only one conformer in PDB
the remaining 75% have at least two conformers with RMSD >0.6A
up to 40 conformers found in some cases
represents natural conformational distribution, depending on protein function
no protein can be described by just one conformation!
tip of the iceberg: information on conformational diversity will be the standard of the future created at: prezi.com motivation: