1qsh: Difference between revisions

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New page: left|200px<br /> <applet load="1qsh" size="450" color="white" frame="true" align="right" spinBox="true" caption="1qsh, resolution 1.70Å" /> '''MAGNESIUM(II)-AND Z...
 
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[[Image:1qsh.gif|left|200px]]<br />
<applet load="1qsh" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1qsh, resolution 1.70&Aring;" />
'''MAGNESIUM(II)-AND ZINC(II)-PROTOPORPHYRIN IX'S STABILIZE THE LOWEST OXYGEN AFFINITY STATE OF HUMAN HEMOGLOBIN EVEN MORE STRONGLY THAN DEOXYHEME'''<br />


==Overview==
==MAGNESIUM(II)-AND ZINC(II)-PROTOPORPHYRIN IX'S STABILIZE THE LOWEST OXYGEN AFFINITY STATE OF HUMAN HEMOGLOBIN EVEN MORE STRONGLY THAN DEOXYHEME==
Studies of oxygen equilibrium properties of Mg(II)-Fe(II) and, Zn(II)-Fe(II) hybrid hemoglobins (i.e. alpha2(Fe)beta2(M) and, alpha2(M)beta2(Fe); M=Mg(II), Zn(II) (neither of these closed-shell metal, ions binds oxygen or carbon monoxide)) are reported along with the X-ray, crystal structures of alpha2(Fe)beta2(Mg) with and without CO bound. We, found that Mg(II)-Fe(II) hybrids resemble Zn(II)-Fe(II) hybrids very, closely in oxygen equilibrium properties. The Fe(II)-subunits in these, hybrids bind oxygen with very low affinities, and the effect of allosteric, effectors, such as proton and/or inositol hexaphosphate, is relatively, small. We also found a striking similarity in spectrophotometric, properties between Mg(II)-Fe(II) and Zn(II)-Fe(II) hybrids, particularly, the large spectral changes that occur specifically in the metal-containing, beta subunits upon the R-T transition of the hybrids. In crystals, both, alpha2(Fe)beta2(Mg) and alpha2(Fe-CO)beta2(Mg) adopt the quaternary, structure of deoxyhemoglobin. These results, combined with the, re-evaluation of the oxygen equilibrium properties of normal hemoglobin, low-affinity mutants, and metal substituted hybrids, point to a general, tendency of human hemoglobin that when the association equilibrium, constant of hemoglobin for the first binding oxygen molecule (K1), approaches 0.004 mmHg(-1), the cooperativity as well as the effect of, allosteric effectors is virtually abolished. This is indicative of the, existence of a distinct thermodynamic state which determines the lowest, oxygen affinity of human hemoglobin. Moreover, excellent agreement between, the reported oxygen affinity of deoxyhemoglobin in crystals and the lowest, affinity in solution leads us to propose that the classical T structure of, deoxyhemoglobin in the crystals represents the lowest affinity state in, solution.We also survey the oxygen equilibrium properties of various, metal-substituted hybrid hemoglobins studied over the past 20 years in our, laboratory. The bulk of these data are consistent with the Perutz's, trigger mechanism, in that the affinity of a metal hybrid is determined by, the ionic radius of the metal, and also by the steric effect of the distal, ligand, if present. However, there remains a fundamental contradiction, among the oxygen equilibrium properties of the beta substituted hybrid, hemoglobins.
<StructureSection load='1qsh' size='340' side='right'caption='[[1qsh]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1qsh]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QSH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1QSH FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEG:PROTOPORPHYRIN+IX+CONTAINING+MG'>HEG</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1qsh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1qsh OCA], [https://pdbe.org/1qsh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1qsh RCSB], [https://www.ebi.ac.uk/pdbsum/1qsh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1qsh ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/HBA_HUMAN HBA_HUMAN] Defects in HBA1 may be a cause of Heinz body anemias (HEIBAN) [MIM:[https://omim.org/entry/140700 140700]. This is a form of non-spherocytic hemolytic anemia of Dacie type 1. After splenectomy, which has little benefit, basophilic inclusions called Heinz bodies are demonstrable in the erythrocytes. Before splenectomy, diffuse or punctate basophilia may be evident. Most of these cases are probably instances of hemoglobinopathy. The hemoglobin demonstrates heat lability. Heinz bodies are observed also with the Ivemark syndrome (asplenia with cardiovascular anomalies) and with glutathione peroxidase deficiency.<ref>PMID:2833478</ref>  Defects in HBA1 are the cause of alpha-thalassemia (A-THAL) [MIM:[https://omim.org/entry/604131 604131]. The thalassemias are the most common monogenic diseases and occur mostly in Mediterranean and Southeast Asian populations. The hallmark of alpha-thalassemia is an imbalance in globin-chain production in the adult HbA molecule. The level of alpha chain production can range from none to very nearly normal levels. Deletion of both copies of each of the two alpha-globin genes causes alpha(0)-thalassemia, also known as homozygous alpha thalassemia. Due to the complete absence of alpha chains, the predominant fetal hemoglobin is a tetramer of gamma-chains (Bart hemoglobin) that has essentially no oxygen carrying capacity. This causes oxygen starvation in the fetal tissues leading to prenatal lethality or early neonatal death. The loss of three alpha genes results in high levels of a tetramer of four beta chains (hemoglobin H), causing a severe and life-threatening anemia known as hemoglobin H disease. Untreated, most patients die in childhood or early adolescence. The loss of two alpha genes results in mild alpha-thalassemia, also known as heterozygous alpha-thalassemia. Affected individuals have small red cells and a mild anemia (microcytosis). If three of the four alpha-globin genes are functional, individuals are completely asymptomatic. Some rare forms of alpha-thalassemia are due to point mutations (non-deletional alpha-thalassemia). The thalassemic phenotype is due to unstable globin alpha chains that are rapidly catabolized prior to formation of the alpha-beta heterotetramers. Note=Alpha(0)-thalassemia is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.  Defects in HBA1 are the cause of hemoglobin H disease (HBH) [MIM:[https://omim.org/entry/613978 613978]. HBH is a form of alpha-thalassemia due to the loss of three alpha genes. This results in high levels of a tetramer of four beta chains (hemoglobin H), causing a severe and life-threatening anemia. Untreated, most patients die in childhood or early adolescence.<ref>PMID:10569720</ref>
== Function ==
[https://www.uniprot.org/uniprot/HBA_HUMAN HBA_HUMAN] Involved in oxygen transport from the lung to the various peripheral tissues.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/qs/1qsh_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1qsh ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
1QSH 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 and HEG as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1QSH OCA].
*[[Hemoglobin 3D structures|Hemoglobin 3D structures]]
 
== References ==
==Reference==
<references/>
Magnesium(II) and zinc(II)-protoporphyrin IX's stabilize the lowest oxygen affinity state of human hemoglobin even more strongly than deoxyheme., Miyazaki G, Morimoto H, Yun KM, Park SY, Nakagawa A, Minagawa H, Shibayama N, J Mol Biol. 1999 Oct 8;292(5):1121-36. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10512707 10512707]
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Large Structures]]
[[Category: Minagawa, H.]]
[[Category: Minagawa H]]
[[Category: Miyazaki, G.]]
[[Category: Miyazaki G]]
[[Category: Morimoto, H.]]
[[Category: Morimoto H]]
[[Category: Nakagawa, A.]]
[[Category: Nakagawa A]]
[[Category: Park, S.Y.]]
[[Category: Park S-Y]]
[[Category: Shibayama, N.]]
[[Category: Shibayama N]]
[[Category: Yun, K.M.]]
[[Category: Yun K-M]]
[[Category: HEG]]
[[Category: HEM]]
[[Category: hemoglobin; oxygen affinity; allosteric effect; metal substitution; trigger mechanism]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Thu Nov  8 13:16:11 2007''

Latest revision as of 11:17, 14 February 2024

MAGNESIUM(II)-AND ZINC(II)-PROTOPORPHYRIN IX'S STABILIZE THE LOWEST OXYGEN AFFINITY STATE OF HUMAN HEMOGLOBIN EVEN MORE STRONGLY THAN DEOXYHEMEMAGNESIUM(II)-AND ZINC(II)-PROTOPORPHYRIN IX'S STABILIZE THE LOWEST OXYGEN AFFINITY STATE OF HUMAN HEMOGLOBIN EVEN MORE STRONGLY THAN DEOXYHEME

Structural highlights

1qsh is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.7Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

HBA_HUMAN Defects in HBA1 may be a cause of Heinz body anemias (HEIBAN) [MIM:140700. This is a form of non-spherocytic hemolytic anemia of Dacie type 1. After splenectomy, which has little benefit, basophilic inclusions called Heinz bodies are demonstrable in the erythrocytes. Before splenectomy, diffuse or punctate basophilia may be evident. Most of these cases are probably instances of hemoglobinopathy. The hemoglobin demonstrates heat lability. Heinz bodies are observed also with the Ivemark syndrome (asplenia with cardiovascular anomalies) and with glutathione peroxidase deficiency.[1] Defects in HBA1 are the cause of alpha-thalassemia (A-THAL) [MIM:604131. The thalassemias are the most common monogenic diseases and occur mostly in Mediterranean and Southeast Asian populations. The hallmark of alpha-thalassemia is an imbalance in globin-chain production in the adult HbA molecule. The level of alpha chain production can range from none to very nearly normal levels. Deletion of both copies of each of the two alpha-globin genes causes alpha(0)-thalassemia, also known as homozygous alpha thalassemia. Due to the complete absence of alpha chains, the predominant fetal hemoglobin is a tetramer of gamma-chains (Bart hemoglobin) that has essentially no oxygen carrying capacity. This causes oxygen starvation in the fetal tissues leading to prenatal lethality or early neonatal death. The loss of three alpha genes results in high levels of a tetramer of four beta chains (hemoglobin H), causing a severe and life-threatening anemia known as hemoglobin H disease. Untreated, most patients die in childhood or early adolescence. The loss of two alpha genes results in mild alpha-thalassemia, also known as heterozygous alpha-thalassemia. Affected individuals have small red cells and a mild anemia (microcytosis). If three of the four alpha-globin genes are functional, individuals are completely asymptomatic. Some rare forms of alpha-thalassemia are due to point mutations (non-deletional alpha-thalassemia). The thalassemic phenotype is due to unstable globin alpha chains that are rapidly catabolized prior to formation of the alpha-beta heterotetramers. Note=Alpha(0)-thalassemia is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. Defects in HBA1 are the cause of hemoglobin H disease (HBH) [MIM:613978. HBH is a form of alpha-thalassemia due to the loss of three alpha genes. This results in high levels of a tetramer of four beta chains (hemoglobin H), causing a severe and life-threatening anemia. Untreated, most patients die in childhood or early adolescence.[2]

Function

HBA_HUMAN Involved in oxygen transport from the lung to the various peripheral tissues.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Ohba Y, Yamamoto K, Hattori Y, Kawata R, Miyaji T. Hyperunstable hemoglobin Toyama [alpha 2 136(H19)Leu----Arg beta 2]: detection and identification by in vitro biosynthesis with radioactive amino acids. Hemoglobin. 1987;11(6):539-56. PMID:2833478
  2. ↑ Traeger-Synodinos J, Harteveld CL, Kanavakis E, Giordano PC, Kattamis C, Bernini LF. Hb Aghia Sophia [alpha62(E11)Val-->0 (alpha1)], an "in-frame" deletion causing alpha-thalassemia. Hemoglobin. 1999 Nov;23(4):317-24. PMID:10569720

1qsh, resolution 1.70Å

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