************ The 19th Lab Seminar **************************************

Title : Determination of Ligand Pathways in Globins
(Mallory D. Salter et al. : J.Biol.Chem, 287, 33163-33178 (2012).)

Speaker : Shogo Hirao

Date : Thu. Feb. 28th, 1:30 pm

Abstract :
Although molecular dynamics simulations suggest multiple interior path-
ways for O2 entry into and exit from globins, most experiments indicate 
well defined single pathways. In 2001, we highlighted the effects of 
large-to-small amino acid replacements on rates for ligand entry and exit 
onto the three-dimensional structure of sperm whale myoglobin. The re-
sultant map argued strongly for ligand movement through a short channel 
fromthe heme iron to solvent that is gated by the distal histidine (His-
64(E7)) near the solvent edge of the porphyrin ring. In this work, we 
have applied the same mutagenesis mapping strategy to the neuronal mini-
hemoglobin from Cerebratulus lacteus (CerHb),which has a large internal 
tunnel fromthe heme iron to the C-terminal ends of the E and H helices, 
a direction that is 180 degree opposite to the E7 channel. Detailed comparisons 
of the new CerHbmap with expanded results forMb show unambiguously that 
the dominant (>90%) ligand pathway in CerHb is through the internal 
tunnel, and themajor (>75%) ligand pathway in Mb is through the E7 gate. 
These results demonstrate that:
1) mutagenesis mapping can identify internal pathways when they exist; 
2) molecular dynamics simulations need to be refined to address 
discrepancies with experimental observations; 
and 3) alternative pathways have evolved in globins to meet specific 
physiological demands.


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