title: Crystal structure of carbonmonoxy sickle hemoglobin in R-state conformation.
abstract: The fundamental pathophysiology of sickle cell disease is predicated by the polymerization of deoxygenated (T-state) sickle hemoglobin (Hb S) into fibers that distort red blood cells into the characteristic sickle shape. The crystal structure of deoxygenated Hb S (DeoxyHb S) and other studies suggest that the polymer is initiated by a primary interaction between the mutation βVal6 from one Hb S molecule, and a hydrophobic acceptor pocket formed by the residues βAla70, βPhe85 and βLeu88 of an adjacent located Hb S molecule. On the contrary, oxygenated or liganded Hb S does not polymerize or incorporate in the polymer. In this paper we present the crystal structure of carbonmonoxy-ligated sickle Hb (COHb S) in the quaternary classical R-state at 1.76Å. The overall structure and the pathological donor and acceptor environments of COHb S are similar to those of the isomorphous CO-ligated R-state normal Hb (COHb A), but differ significantly from DeoxyHb S as expected. More importantly, the packing of COHb S molecules does not show the typical pathological interaction between βVal6 and the βAla70, βPhe85 and βLeu88 hydrophobic acceptor pocket observed in DeoxyHb S crystal. The structural analysis of COHb S, COHb A and DeoxyHb S provides atomic level insight into why liganded hemoglobin does not form a polymer.
authors.affiliation: Department of Medicinal Chemistry, and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
authors.forename: Mohini S
authors.initials: MS
authors.lastname: Ghatge
authors.affiliation: Department of Medicinal Chemistry, and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
authors.forename: Mostafa H
authors.initials: MH
authors.lastname: Ahmed
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
authors.forename: Abdel Sattar M
authors.initials: AS
authors.lastname: Omar
authors.affiliation: Department of Medicinal Chemistry, and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
authors.forename: Piyusha P
authors.initials: PP
authors.lastname: Pagare
authors.affiliation: Division of Clinical Pathology, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Rosef
authors.affiliation: Department of Medicinal Chemistry, and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, PA 19104, United States.
authors.forename: Osheiza
authors.initials: O
authors.lastname: Abdulmalik
authors.affiliation: Department of Medicinal Chemistry, and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address: msafo@vcu.edu.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Safo
mesh_terms: D000596:Amino Acids; D002263:Carboxyhemoglobin / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006451:Hemoglobin, Sickle / Q000737:chemistry*; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D008024:Ligands; D058105:Polymerization; D020836:Protein Structure, Quaternary
chemical_list: D000596:Amino Acids; D006451:Hemoglobin, Sickle; D006454:Hemoglobins; D008024:Ligands; D002263:Carboxyhemoglobin
keywords: Allosteric; Crystal structure; Hemoglobin; Mutation; R-state; Sickle cell disease