5U3I

CRYSTAL STRUCTURE OF CARBONMONOXY HEMOGLOBIN S (LIGANDED SICKLE CELL HEMOGLOBIN) COMPLEXED WITH GBT compound 31

Summary for 5U3I

• Entry DOI: 10.2210/pdb5u3i/pdb
• Related: 5UFJ
• Descriptor: Hemoglobin subunit alpha, Hemoglobin subunit beta, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• Functional Keywords: r2 quaternary state, oxygen transport
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 64951.51

Authors

Partridge, J.R.,Choy, R.M.,Li, Z.,Metcalf, B. (deposition date: 2016-12-02, release date: 2017-02-22, Last modification date: 2023-10-04)

Primary citation

Metcalf, B.,Chuang, C.,Dufu, K.,Patel, M.P.,Silva-Garcia, A.,Johnson, C.,Lu, Q.,Partridge, J.R.,Patskovska, L.,Patskovsky, Y.,Almo, S.C.,Jacobson, M.P.,Hua, L.,Xu, Q.,Gwaltney, S.L.,Yee, C.,Harris, J.,Morgan, B.P.,James, J.,Xu, D.,Hutchaleelaha, A.,Paulvannan, K.,Oksenberg, D.,Li, Z.
Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin.
ACS Med Chem Lett, 8:321-326, 2017

PubMed Abstract: We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, binds with a 1:1 stoichiometry. Compound is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 () is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).

PubMed: 28337324
DOI: 10.1021/acsmedchemlett.6b00491

Experimental method

X-RAY DIFFRACTION (1.95 Å)