1vwt: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:1vwt.gif|left|200px]]<br /> | [[Image:1vwt.gif|left|200px]]<br /><applet load="1vwt" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1vwt" size=" | |||
caption="1vwt, resolution 1.9Å" /> | caption="1vwt, resolution 1.9Å" /> | ||
'''T STATE HUMAN HEMOGLOBIN [ALPHA V96W], ALPHA AQUOMET, BETA DEOXY'''<br /> | '''T STATE HUMAN HEMOGLOBIN [ALPHA V96W], ALPHA AQUOMET, BETA DEOXY'''<br /> | ||
==Overview== | ==Overview== | ||
One of the most promising approaches for the development of a synthetic | One of the most promising approaches for the development of a synthetic blood substitute has been the engineering of novel mutants of human hemoglobin (Hb) A which maintain cooperativity, but possess lowered oxygen affinity. We describe here two crystal structures of one such potential blood substitute, recombinant (r) Hb(alpha 96Val-->Trp), refined to 1.9 A resolution in an alpha-aquomet, beta-deoxy T-state, and to 2.5 A resolution in a carbonmonoxy R-state. On the basis of molecular dynamics simulations, a particular conformation had been predicted for the engineered Trp residue, and the lowered oxygen affinity had been attributed to a stabilization of the deoxy T-state interface by alpha 96Trp-beta 99Asp hydrogen bonds. Difference Fourier maps of the T-state structure clearly show that alpha 96Trp is in a conformation different from that predicted by the simulation, with its indole side chain directed away from the interface and into the central cavity. In this conformation, the indole nitrogen makes novel water-mediated hydrogen bonds across the T-state interface with beta 101Glu. We propose that these water-mediated hydrogen bonds are the structural basis for the lowered oxygen affinity of rHb(alpha 96Val-->Trp), and discuss the implications of these findings for future molecular dynamics studies and the design of Hb mutants. | ||
==Disease== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
1VWT is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and HEM as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 1VWT is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=HEM:'>HEM</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1VWT OCA]. | ||
==Reference== | ==Reference== | ||
| Line 17: | Line 16: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Almo, S | [[Category: Almo, S C.]] | ||
[[Category: Ho, C.]] | [[Category: Ho, C.]] | ||
[[Category: Ho, N | [[Category: Ho, N T.]] | ||
[[Category: Puius, Y | [[Category: Puius, Y A.]] | ||
[[Category: Zou, M.]] | [[Category: Zou, M.]] | ||
[[Category: HEM]] | [[Category: HEM]] | ||
| Line 33: | Line 32: | ||
[[Category: oxygen transport]] | [[Category: oxygen transport]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:38:30 2008'' | ||
Revision as of 16:38, 21 February 2008
|
T STATE HUMAN HEMOGLOBIN [ALPHA V96W], ALPHA AQUOMET, BETA DEOXY
OverviewOverview
One of the most promising approaches for the development of a synthetic blood substitute has been the engineering of novel mutants of human hemoglobin (Hb) A which maintain cooperativity, but possess lowered oxygen affinity. We describe here two crystal structures of one such potential blood substitute, recombinant (r) Hb(alpha 96Val-->Trp), refined to 1.9 A resolution in an alpha-aquomet, beta-deoxy T-state, and to 2.5 A resolution in a carbonmonoxy R-state. On the basis of molecular dynamics simulations, a particular conformation had been predicted for the engineered Trp residue, and the lowered oxygen affinity had been attributed to a stabilization of the deoxy T-state interface by alpha 96Trp-beta 99Asp hydrogen bonds. Difference Fourier maps of the T-state structure clearly show that alpha 96Trp is in a conformation different from that predicted by the simulation, with its indole side chain directed away from the interface and into the central cavity. In this conformation, the indole nitrogen makes novel water-mediated hydrogen bonds across the T-state interface with beta 101Glu. We propose that these water-mediated hydrogen bonds are the structural basis for the lowered oxygen affinity of rHb(alpha 96Val-->Trp), and discuss the implications of these findings for future molecular dynamics studies and the design of Hb mutants.
DiseaseDisease
Known diseases associated with this structure: Erythremias, alpha- OMIM:[141800], Erythremias, beta- OMIM:[141900], Erythrocytosis OMIM:[141850], HPFH, deletion type OMIM:[141900], Heinz body anemia OMIM:[141850], Heinz body anemias, alpha- OMIM:[141800], Heinz body anemias, beta- OMIM:[141900], Hemoglobin H disease OMIM:[141850], Hypochromic microcytic anemia OMIM:[141850], Methemoglobinemias, alpha- OMIM:[141800], Methemoglobinemias, beta- OMIM:[141900], Sickle cell anemia OMIM:[141900], Thalassemia, alpha- OMIM:[141850], Thalassemia-beta, dominant inclusion-body OMIM:[141900], Thalassemias, alpha- OMIM:[141800], Thalassemias, beta- OMIM:[141900]
About this StructureAbout this Structure
1VWT is a Protein complex structure of sequences from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Novel water-mediated hydrogen bonds as the structural basis for the low oxygen affinity of the blood substitute candidate rHb(alpha 96Val-->Trp)., Puius YA, Zou M, Ho NT, Ho C, Almo SC, Biochemistry. 1998 Jun 30;37(26):9258-65. PMID:9649306
Page seeded by OCA on Thu Feb 21 15:38:30 2008