PDBsum entry 7lmq

Immune system

PDB id: 7lmq

Contents

Protein chains

215 a.a.

Ligands

9ZW

PO4 ×2

Waters ×511

PDB id:

7lmq

Name:

Immune system

Title:

Structure of full-length human lambda-6a light chain jto in complex with stabilizer 62 [4-methyl-3-(morpholinomethyl)-7-(1-phenylethoxy)- 2h-chromen-2-one]

Structure:

Jto light chain. Chain: a, b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.91Å R-factor: 0.163 R-free: 0.203

Authors:

N.L.Yan,I.A.Wilson,J.W.Kelly

Key ref:

N.L.Yan et al. (2021). Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design. J Med Chem, 64, 6273-6299. PubMed id: 33939422 DOI: 10.1021/acs.jmedchem.1c00339

Date:

05-Feb-21 Release date: 19-May-21

Protein chains

No UniProt id for this chain

Struc: 215 a.a.

DOI no: 10.1021/acs.jmedchem.1c00339

J Med Chem 64:6273-6299 (2021)

PubMed id: 33939422

Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design.

N.L.Yan, D.Santos-Martins, R.Nair, A.Chu, I.A.Wilson, K.A.Johnson, S.Forli, G.J.Morgan, H.M.Petrassi, J.W.Kelly.

ABSTRACT

In immunoglobulin light-chain (LC) amyloidosis, transient unfolding or unfolding and proteolysis enable aggregation of LC proteins, causing potentially fatal organ damage. A drug that kinetically stabilizes LCs could suppress aggregation; however, LC sequences are variable and have no natural ligands, hindering drug development efforts. We previously identified high-throughput screening hits that bind to a site at the interface between the two variable domains of the LC homodimer. We hypothesized that extending the stabilizers beyond this initially characterized binding site would improve affinity. Here, using protease sensitivity assays, we identified stabilizers that can be divided into four substructures. Some stabilizers exhibit nanomolar EC₅₀ values, a 3000-fold enhancement over the screening hits. Crystal structures reveal a key π-π stacking interaction with a conserved tyrosine residue that was not utilized by the screening hits. These data provide a foundation for developing LC stabilizers with improved binding selectivity and enhanced physicochemical properties.