PDBsum entry 1qxe

Oxygen storage/transport

PDB id: 1qxe

Contents

Protein chains

141 a.a. *

146 a.a. *

Ligands

SO4 ×7

OXY-HEM ×4

FUX ×2

Waters ×537

* Residue conservation analysis

PDB id:

1qxe

Name:

Oxygen storage/transport

Title:

Structural basis for the potent antisickling effect of a novel class of 5-membered heterocyclic aldehydic compounds

Structure:

Hemoglobin alpha chain. Chain: a, c. Fragment: alpha chain. Hemoglobin beta chain. Chain: b, d. Fragment: beta chain

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: blood. Cell: erythrocytes. Cell: erythrocytes

Biol. unit:

Tetramer (from PQS)

Resolution:

1.85Å R-factor: 0.184 R-free: 0.223

Authors:

M.K.Safo,O.Abdulmalik,R.Danso-Danquah,S.Nokuri,G.S.Joshi,F.N.Musayev, T.Asakura,D.J.Abraham

Key ref:

M.K.Safo et al. (2004). Structural basis for the potent antisickling effect of a novel class of five-membered heterocyclic aldehydic compounds. J Med Chem, 47, 4665-4676. PubMed id: 15341482 DOI: 10.1021/jm0498001

Date:

05-Sep-03 Release date: 16-Sep-03

Protein chains

P69905  (HBA_HUMAN) -  Hemoglobin subunit alpha from Homo sapiens

Seq: 142 a.a.

Struc: 141 a.a.

Protein chains

P68871  (HBB_HUMAN) -  Hemoglobin subunit beta from Homo sapiens

Seq: 147 a.a.

Struc: 146 a.a.

DOI no: 10.1021/jm0498001

J Med Chem 47:4665-4676 (2004)

PubMed id: 15341482

Structural basis for the potent antisickling effect of a novel class of five-membered heterocyclic aldehydic compounds.

M.K.Safo, O.Abdulmalik, R.Danso-Danquah, J.C.Burnett, S.Nokuri, G.S.Joshi, F.N.Musayev, T.Asakura, D.J.Abraham.

ABSTRACT

Naturally occurring five-membered heterocyclic aldehydes, including 5-hydroxymethyl-2-furfural, increase the oxygen affinity of hemoglobin (Hb) and strongly inhibit the sickling of homozygous sickle red blood (SS) cells. X-ray studies of Hb complexed with these compounds indicate that they form Schiff base adducts in a symmetrical fashion with the N-terminal alphaVal1 nitrogens of Hb. Interestingly, two cocrystal types were isolated during crystallization experiments with deoxygenated Hb (deoxyHb): one crystal type was composed of the low-affinity or tense (T) state Hb quaternary structure; the other crystal type was composed of high-affinity or relaxed state Hb (with a R2 quaternary structure). The R2 crystal appears to be formed as a result of the aldehydes binding to fully or partially ligated Hb in the deoxyHb solution. Repeated attempts to crystallize the compounds with liganded Hb failed, except on rare occasions when very few R state crystals were obtained. Oxygen equilibrium, high performance liquid chromatography (HPLC), antisickling, and X-ray studies suggest that the examined heterocyclic aldehydes may be acting to prevent polymerization of sickle hemoglobin (HbS) by binding to and stabilizing liganded Hb in the form of R2 and/or various relaxed state Hbs, as well as binding to and destabilizing unliganded T state Hb. The proposed mechanism may provide a general model for the antisickling effects of aldehyde containing small molecules that bind to N-terminal alphaVal1 nitrogens of Hb. The examined compounds also represent a new class of potentially therapeutic agents for treating sickle cell disease (SCD).