5E83

CRYSTAL STRUCTURE OF CARBONMONOXY HEMOGLOBIN S (LIGANDED SICKLE CELL HEMOGLOBIN) COMPLEXED WITH GBT440, CO-CRYSTALLIZATION EXPERIMENT

Summary for 5E83

• Entry DOI: 10.2210/pdb5e83/pdb
• Descriptor: Hemoglobin subunit alpha, Hemoglobin subunit beta, PROTOPORPHYRIN IX CONTAINING FE, ... (8 entities in total)
• Functional Keywords: mutant human hemoglobin s[betae6v], r2 quaternary state, oxygen transport
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 65301.92

Authors

Patskovska, L.,Patskovsky, Y.,Bonanno, J.B.,Almo, S.C. (deposition date: 2015-10-13, release date: 2016-07-20, Last modification date: 2024-11-20)

Primary citation

Oksenberg, D.,Dufu, K.,Patel, M.P.,Chuang, C.,Li, Z.,Xu, Q.,Silva-Garcia, A.,Zhou, C.,Hutchaleelaha, A.,Patskovska, L.,Patskovsky, Y.,Almo, S.C.,Sinha, U.,Metcalf, B.W.,Archer, D.R.
GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.
Br.J.Haematol., 175:141-153, 2016

PubMed Abstract: A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease-modifying agent in sickle cell patients.

PubMed: 27378309
DOI: 10.1111/bjh.14214

Experimental method

X-RAY DIFFRACTION (1.8 Å)