1y5f: Difference between revisions
New page: left|200px<br /> <applet load="1y5f" size="450" color="white" frame="true" align="right" spinBox="true" caption="1y5f, resolution 2.14Å" /> '''T-To-T(High) quater... |
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==Overview== | ==Overview== | ||
A detailed description of hemoglobin cooperativity requires knowledge of, the dimer-dimer interactions responsible for the low ligand affinity of, the quaternary-T tetramer, the "quaternary-T constraints", along with, stereochemical pathways that specify how ligand binding disrupts these, quaternary constraints. The recent mutagenic screen of Noble et al., [Noble, R. W., et al. (2001) Biochemistry 40, 12357-12368] has identified, the major region of quaternary constraint to be a cluster of residues at, the alpha1beta2 interface that is centered at Trp37beta. In this paper, crystallographic studies are presented for most of the mutant hemoglobins, studied by Noble et al. These crystallographic experiments identify, structural transitions-referred to as T-to-T(High) transitions-between the, quaternary-T structure of wild-type deoxyhemoglobin and an ensemble of, related T-like quaternary structures that are induced by some mutations in, the Trp37beta cluster and/or by exposing crystals of wild-type or mutant, deoxyhemoglobins to oxygen. The T-to-T(High) quaternary transitions, consist of a rotation of the alpha1beta1 dimer relative to the alpha2beta2, dimer as well as a coupled alphabeta dimer bending component that consists, of a small rotation of the alpha1 subunit relative to the beta1 subunit, (and a symmetry related rotation of the alpha2 subunit relative to the, beta2 subunit). In addition, differences in subunit tertiary structure, associated with the T-to-T(High) transitions suggest two stereochemical, pathways (one associated with the alpha subunits and one associated with, the betasubunits) by which ligand binding specifically disrupts quaternary, constraints in the Trp37beta cluster. In the alpha subunits, ligand, binding induces a shift of the heme iron producing tension in a chain of, covalent bonds that extends from the Fe-N(epsilon)(2)His(F8)alpha1 bond to, the peptide backbone bonds of residues His87(F8)alpha1 and, Ala88(F9)alpha1. This tension induces an alpha-to-pi transition in the, COOH-terminal end of the F-helix that shifts the beta-carbon of, Ala88alpha1 by approximately 1.5 A directly into the side chain of, Tyr140alpha1 (a key residue in the Trp37beta2 cluster). Collectively these, structural changes constitute a relatively short pathway by which ligand, binding forces Tyr140alpha1 into the alpha1beta2 interface disrupting, quaternary constraints associated with the Trp37beta2 cluster. In the beta, subunits, our analysis suggests a more extended energy transduction, pathway in which ligand-induced beta1-heme movement triggers tertiary, changes in the beta1 subunit that promote alpha1beta1 dimer bending that, disrupts quaternary constraints in the Trp37beta2 cluster at the, alpha1beta2 interface. | A detailed description of hemoglobin cooperativity requires knowledge of, the dimer-dimer interactions responsible for the low ligand affinity of, the quaternary-T tetramer, the "quaternary-T constraints", along with, stereochemical pathways that specify how ligand binding disrupts these, quaternary constraints. The recent mutagenic screen of Noble et al., [Noble, R. W., et al. (2001) Biochemistry 40, 12357-12368] has identified, the major region of quaternary constraint to be a cluster of residues at, the alpha1beta2 interface that is centered at Trp37beta. In this paper, crystallographic studies are presented for most of the mutant hemoglobins, studied by Noble et al. These crystallographic experiments identify, structural transitions-referred to as T-to-T(High) transitions-between the, quaternary-T structure of wild-type deoxyhemoglobin and an ensemble of, related T-like quaternary structures that are induced by some mutations in, the Trp37beta cluster and/or by exposing crystals of wild-type or mutant, deoxyhemoglobins to oxygen. The T-to-T(High) quaternary transitions, consist of a rotation of the alpha1beta1 dimer relative to the alpha2beta2, dimer as well as a coupled alphabeta dimer bending component that consists, of a small rotation of the alpha1 subunit relative to the beta1 subunit, (and a symmetry related rotation of the alpha2 subunit relative to the, beta2 subunit). In addition, differences in subunit tertiary structure, associated with the T-to-T(High) transitions suggest two stereochemical, pathways (one associated with the alpha subunits and one associated with, the betasubunits) by which ligand binding specifically disrupts quaternary, constraints in the Trp37beta cluster. In the alpha subunits, ligand, binding induces a shift of the heme iron producing tension in a chain of, covalent bonds that extends from the Fe-N(epsilon)(2)His(F8)alpha1 bond to, the peptide backbone bonds of residues His87(F8)alpha1 and, Ala88(F9)alpha1. This tension induces an alpha-to-pi transition in the, COOH-terminal end of the F-helix that shifts the beta-carbon of, Ala88alpha1 by approximately 1.5 A directly into the side chain of, Tyr140alpha1 (a key residue in the Trp37beta2 cluster). Collectively these, structural changes constitute a relatively short pathway by which ligand, binding forces Tyr140alpha1 into the alpha1beta2 interface disrupting, quaternary constraints associated with the Trp37beta2 cluster. In the beta, subunits, our analysis suggests a more extended energy transduction, pathway in which ligand-induced beta1-heme movement triggers tertiary, changes in the beta1 subunit that promote alpha1beta1 dimer bending that, disrupts quaternary constraints in the Trp37beta2 cluster at the, alpha1beta2 interface. | ||
==Disease== | |||
Known diseases associated with this structure: Erythremias, alpha- OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141800 141800]], Erythremias, beta- OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141900 141900]], Erythrocytosis OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141850 141850]], HPFH, deletion type OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141900 141900]], Heinz body anemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141850 141850]], Heinz body anemias, alpha- OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141800 141800]], Heinz body anemias, beta- OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141900 141900]], Hemoglobin H disease OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141850 141850]], Hypochromic microcytic anemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141850 141850]], Methemoglobinemias, alpha- OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141800 141800]], Methemoglobinemias, beta- OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141900 141900]], Sickle cell anemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141900 141900]], Thalassemia, alpha- OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141850 141850]], Thalassemia-beta, dominant inclusion-body OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141900 141900]], Thalassemias, alpha- OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141800 141800]], Thalassemias, beta- OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141900 141900]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: hemoglobin mutant]] | [[Category: hemoglobin mutant]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:15:05 2007'' | ||
Revision as of 21:08, 12 November 2007
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T-To-T(High) quaternary transitions in human hemoglobin: betaL96A deoxy low-salt (1 test set)
OverviewOverview
A detailed description of hemoglobin cooperativity requires knowledge of, the dimer-dimer interactions responsible for the low ligand affinity of, the quaternary-T tetramer, the "quaternary-T constraints", along with, stereochemical pathways that specify how ligand binding disrupts these, quaternary constraints. The recent mutagenic screen of Noble et al., [Noble, R. W., et al. (2001) Biochemistry 40, 12357-12368] has identified, the major region of quaternary constraint to be a cluster of residues at, the alpha1beta2 interface that is centered at Trp37beta. In this paper, crystallographic studies are presented for most of the mutant hemoglobins, studied by Noble et al. These crystallographic experiments identify, structural transitions-referred to as T-to-T(High) transitions-between the, quaternary-T structure of wild-type deoxyhemoglobin and an ensemble of, related T-like quaternary structures that are induced by some mutations in, the Trp37beta cluster and/or by exposing crystals of wild-type or mutant, deoxyhemoglobins to oxygen. The T-to-T(High) quaternary transitions, consist of a rotation of the alpha1beta1 dimer relative to the alpha2beta2, dimer as well as a coupled alphabeta dimer bending component that consists, of a small rotation of the alpha1 subunit relative to the beta1 subunit, (and a symmetry related rotation of the alpha2 subunit relative to the, beta2 subunit). In addition, differences in subunit tertiary structure, associated with the T-to-T(High) transitions suggest two stereochemical, pathways (one associated with the alpha subunits and one associated with, the betasubunits) by which ligand binding specifically disrupts quaternary, constraints in the Trp37beta cluster. In the alpha subunits, ligand, binding induces a shift of the heme iron producing tension in a chain of, covalent bonds that extends from the Fe-N(epsilon)(2)His(F8)alpha1 bond to, the peptide backbone bonds of residues His87(F8)alpha1 and, Ala88(F9)alpha1. This tension induces an alpha-to-pi transition in the, COOH-terminal end of the F-helix that shifts the beta-carbon of, Ala88alpha1 by approximately 1.5 A directly into the side chain of, Tyr140alpha1 (a key residue in the Trp37beta2 cluster). Collectively these, structural changes constitute a relatively short pathway by which ligand, binding forces Tyr140alpha1 into the alpha1beta2 interface disrupting, quaternary constraints associated with the Trp37beta2 cluster. In the beta, subunits, our analysis suggests a more extended energy transduction, pathway in which ligand-induced beta1-heme movement triggers tertiary, changes in the beta1 subunit that promote alpha1beta1 dimer bending that, disrupts quaternary constraints in the Trp37beta2 cluster at the, alpha1beta2 interface.
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
1Y5F is a Protein complex structure of sequences from Homo sapiens with HEM as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Crystallographic evidence for a new ensemble of ligand-induced allosteric transitions in hemoglobin: the T-to-T(high) quaternary transitions., Kavanaugh JS, Rogers PH, Arnone A, Biochemistry. 2005 Apr 26;44(16):6101-21. PMID:15835899
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