1abw: Difference between revisions
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[[Image:1abw.gif|left|200px]]<br /> | [[Image:1abw.gif|left|200px]]<br /><applet load="1abw" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1abw" size=" | |||
caption="1abw, resolution 2.0Å" /> | caption="1abw, resolution 2.0Å" /> | ||
'''DEOXY RHB1.1 (RECOMBINANT HEMOGLOBIN)'''<br /> | '''DEOXY RHB1.1 (RECOMBINANT HEMOGLOBIN)'''<br /> | ||
==Overview== | ==Overview== | ||
BACKGROUND:. Potential blood substitutes can be based on hemoglobin. Two | BACKGROUND:. Potential blood substitutes can be based on hemoglobin. Two problems must be overcome with acellular hemoglobin-based blood substitutes, however: the oxygen affinity of purified human hemoglobin is too high for it to deliver oxygen to tissues, and hemoglobin tetramers dissociate into alphabeta dimers that can cause kidney damage. A modified form of hemoglobin, rHb 1.1, has reduced oxygen affinity as the result of an Asnbeta 108-->Lys mutation, and dimerization is prevented by the insertion of a glycine residue between the sequences of the normal alpha chains to produce one covalently continuous di-alpha-chain. Determination of the structure of rHb 1.1 would provide structure-based explanations for the altered properties of rHb 1.1. RESULTS:. We determined the structures of the deoxy form of rHb 1.1 at 2.0 resolution and of cyanomet-rHb 1.1 at 2.6 resolution. Deoxy-rHb 1.1 adopts the classic 'T state' quaternary structure, but cyanomet-rHb 1.1 adopts a novel quanternary structure, the B state. The most striking feature of the tertiary structures is a charged hydrogen bond involving Lysbeta 108 that is broken in the T-->B state transition. The glycine bridge within the di-alpha-chain is well defined in both structures and appears to cause adoption of the B state instead of the previously observed ligand-bound quaternary structures R or Y/R2. CONCLUSIONS:. A charged hydrogen bond between Lysbeta 108 and Tyrbeta35 is broken in the transition between the deoxy and ligand-bound forms of rHb 1.1. This structural change reduces the oxygen affinity of rHb 1.1 by changing the relative stability of deoxy and ligand-bound states. Furthermore, our observations highlight the importance of small conformational changes in allosteric proteins, even in their most rigid domains. Three ligand-bound quaternary structures of hemoglobin (R, Y/R2 and B) have now been described. In contrast, only one quaternary structure has been observed for deoxyhemoglobin (T). The structural degeneracy of the high oxygen affinity form of hemoglobin is an important reminder that allosteric proteins may have multiple quaternary structures that are functionally very similar. This degeneracy of quaternary structures has important implications for the regulation of allosteric proteins, because different quaternary structures may be stabilized by different allosteric effectors. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1ABW 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 HEM as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 1ABW 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=HEM:'>HEM</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ABW OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Kroeger, K | [[Category: Kroeger, K S.]] | ||
[[Category: Kundrot, C | [[Category: Kundrot, C E.]] | ||
[[Category: HEM]] | [[Category: HEM]] | ||
[[Category: erythrocyte]] | [[Category: erythrocyte]] | ||
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[[Category: respiratory protein]] | [[Category: respiratory protein]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:42:55 2008'' | ||
Revision as of 12:42, 21 February 2008
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DEOXY RHB1.1 (RECOMBINANT HEMOGLOBIN)
OverviewOverview
BACKGROUND:. Potential blood substitutes can be based on hemoglobin. Two problems must be overcome with acellular hemoglobin-based blood substitutes, however: the oxygen affinity of purified human hemoglobin is too high for it to deliver oxygen to tissues, and hemoglobin tetramers dissociate into alphabeta dimers that can cause kidney damage. A modified form of hemoglobin, rHb 1.1, has reduced oxygen affinity as the result of an Asnbeta 108-->Lys mutation, and dimerization is prevented by the insertion of a glycine residue between the sequences of the normal alpha chains to produce one covalently continuous di-alpha-chain. Determination of the structure of rHb 1.1 would provide structure-based explanations for the altered properties of rHb 1.1. RESULTS:. We determined the structures of the deoxy form of rHb 1.1 at 2.0 resolution and of cyanomet-rHb 1.1 at 2.6 resolution. Deoxy-rHb 1.1 adopts the classic 'T state' quaternary structure, but cyanomet-rHb 1.1 adopts a novel quanternary structure, the B state. The most striking feature of the tertiary structures is a charged hydrogen bond involving Lysbeta 108 that is broken in the T-->B state transition. The glycine bridge within the di-alpha-chain is well defined in both structures and appears to cause adoption of the B state instead of the previously observed ligand-bound quaternary structures R or Y/R2. CONCLUSIONS:. A charged hydrogen bond between Lysbeta 108 and Tyrbeta35 is broken in the transition between the deoxy and ligand-bound forms of rHb 1.1. This structural change reduces the oxygen affinity of rHb 1.1 by changing the relative stability of deoxy and ligand-bound states. Furthermore, our observations highlight the importance of small conformational changes in allosteric proteins, even in their most rigid domains. Three ligand-bound quaternary structures of hemoglobin (R, Y/R2 and B) have now been described. In contrast, only one quaternary structure has been observed for deoxyhemoglobin (T). The structural degeneracy of the high oxygen affinity form of hemoglobin is an important reminder that allosteric proteins may have multiple quaternary structures that are functionally very similar. This degeneracy of quaternary structures has important implications for the regulation of allosteric proteins, because different quaternary structures may be stabilized by different allosteric effectors.
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
1ABW is a Protein complex structure of sequences from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Structures of a hemoglobin-based blood substitute: insights into the function of allosteric proteins., Kroeger KS, Kundrot CE, Structure. 1997 Feb 15;5(2):227-37. PMID:9032082
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