1qi8
From Proteopedia
DEOXYGENATED STRUCTURE OF A DISTAL POCKET HEMOGLOBIN MUTANT
Structural highlights
DiseaseHBA_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] FunctionHBA_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. Publication Abstract from PubMedFunctional and structural studies on hemoglobin and myoglobin from different animals and engineered variants have enlightened the great importance of the physico-chemical properties of the side-chains at topological position B10 and E7. These residues proved to be crucial to the discrimination and stabilisation of gaseous ligands. In view of the data obtained on the high oxygen affinity hemoglobin from Ascaris worms and a new mutant of sperm whale myoglobin, we selected the two mutations Leu B10-->Tyr and His E7-->Gln as potentially relevant to control ligand binding parameters in the alpha and beta-chains of human hemoglobin. Here, we present an investigation of three new mutants: HbalphaYQ (alpha2YQbeta2A), HbbetaYQ (alpha2Abeta2YQ) and HbalphabetaYQ (alpha2YQbeta2YQ). They are characterised by a very low reactivity for NO, O2 and CO, and a reduced cooperativity. Their functional properties are not inconsistent with the behaviour expected for a two-state allosteric model. Proteins with these substitutions may be considered as candidates for the synthesis of a possible "blood substitute", which should yield an O2 adduct stable to autoxidation and slowly reacting with NO. The mutant HbalphabetaYQ is particularly interesting because the rate of reaction of NO with the oxy and deoxy derivatives is reduced. A structural interpretation of our data is presented based on the 3D structure of deoxy HbalphabetaYQ determined by crystallography at 1.8 A resolution. Modulation of ligand binding in engineered human hemoglobin distal pocket.,Miele AE, Santanche S, Travaglini-Allocatelli C, Vallone B, Brunori M, Bellelli A J Mol Biol. 1999 Jul 9;290(2):515-24. PMID:10390349[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
