Title: Hemoglobin Presented to Bioinformatic MN1 10 p course, Spring term 2006 by Amirah Khan With acknowlegment to Miriam Ge
1HemoglobinPresented to Bioinformatic MN1 10 p
course, Spring term 2006 by Amirah Khan With
acknowlegment to Miriam Geörg Björn Garpefjord
2Hemoglobin 3D Structure
Tetrameric complex a2b2 Chain A Chain
C Chain B Chain D 1 heme group per
subunit/chain CATH Classification C Mainly Alpha
(1) A Orthogonal Bundle T Globin-like H Globin
3How may the structure of hemoglobin be
stabilised?
4N-capping of helices
- Helix Ala53 Ala71
- Removal of Ala53
- Replaced by Asp, negatively charged
- ? Reduced dipole moment
5N-capping of helices
- Reduced dipole moment in helix
- Indication of H-bond to Gly57
- More stable?
6Reducing the Flexibility of the Main Chain
- Stabilization of exposed loop by mutating Gly
to Pro - Mutation G51 P
7Stabilizing the Quartenary Structure
- The hemoglobin tetramer consists of 2 ab dimers.
- The interface between those 2 dimers is important
for flexibility and funcionality. - Stabilization of the ab dimers by creation of
disulfide-bonds between the subunits - Mutations
- a chain Ala 123 Cys
- b chain Val 33 Cys
8Stabilizing the Quartenary Structure
9Stabilizing the Hydrophobic Core
- The main pocket of each chain is occupied by the
heme group which is essential for function. - Mutations in these pockets might interfer with
heme binding and thus oxygen transport.
10Increasing the Oxygen - Affinity
- In nature there exist different forms of
hemoglobin - Adult hemoglobin (a2b2)
- Fetal hemoglobin (a2g2)
with higher oxygen affinity - ? Increase of Oxygen Affinity by mutating the
aas close to the coordinative His 92 to the
corresponding aas in fHb
Coordinative Histidine
11Increasing the Oxygen - Affinity
12Stabilization vs Flexibility
- Stabilized Structure
- Industrial Applications?
- Conserved Structure
- Optimized by evolution!!!
- Flexibility of subunits needed for protein
function - Induced fit conformational change after binding
of first O2 leads to increased affinity for
following O2 molecules - Large pockets occupied by essential heme group
- Single aa exchange in Sickle Cell Anemia causes
aggregation of hemoglobin