6B1K

Macrophage Migration Inhibitory Factor in Complex with a Naphthyridinone Inhibitor (3a)

PDB DOI: https://doi.org/10.2210/pdb6B1K/pdb

Classification: ISOMERASE/ISOMERASE inhibitor
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2017-09-18 Released: 2018-01-03
Deposition Author(s): Krimmer, S.G., Robertson, M.J., Jorgensen, W.L.
Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.17 Å
R-Value Free: 0.154
R-Value Work: 0.135
R-Value Observed: 0.136

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor.

Dawson, T.K., Dziedzic, P., Robertson, M.J., Cisneros, J.A., Krimmer, S.G., Newton, A.S., Tirado-Rives, J., Jorgensen, W.L.

(2017) ACS Med Chem Lett 8: 1287-1291

PubMed: 29259749 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.7b00384
Primary Citation of Related Structures:
6B1C, 6B1K, 6B2C

PubMed Abstract:
Coordination of the ammonium group of Lys32 in the active site of human macrophage migration inhibitory factor (MIF) using a 1,7-naphthyridin-8-one instead of a quinoline is investigated. Both gas- and aqueous-phase DFT calculations for model systems indicate potential benefits for the added hydrogen bond with the lactam carbonyl group, while FEP results are neutral. Three crystal structures are reported for complexes of MIF with 3a , 4a , and 4b , which show that the desired hydrogen bond is formed with O-N distances of 2.8-3.0 Å. Compound 4b is the most potent new MIF inhibitor with K _i and K _d values of 90 and 94 nM; it also has excellent aqueous solubility, 288 μg/mL. Consistent with the FEP results, the naphthyridinones are found to have similar potency as related quinolines in spite of the additional protein-ligand hydrogen bond.

Organizational Affiliation

Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.

Macromolecule Content

Total Structure Weight: 38.5 kDa
Atom Count: 3,288
Modelled Residue Count: 342
Deposited Residue Count: 342
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Macrophage migration inhibitory factor	A, B, C	114	Homo sapiens	Mutation(s): 0 Gene Names: MIF, GLIF, MMIF EC: 5.3.2.1 (PDB Primary Data), 5.3.3.12 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P14174 (Homo sapiens) Explore P14174 Go to UniProtKB: P14174
PHAROS: P14174 GTEx: ENSG00000240972
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P14174
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
C9G Query on C9G Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain G [auth B] SDF format, chain I [auth C] MOL2 format, chain D [auth A] MOL2 format, chain G [auth B] MOL2 format, chain I [auth C] mmCIF format, chain D [auth A] mmCIF format, chain G [auth B] mmCIF format, chain I [auth C]	D [auth A], G [auth B], I [auth C]	2-[1-(4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl]-7-methyl-1,7-naphthyridin-8(7H)-one C₁₇ H₁₃ N₅ O₂ KANBQBQJUNGFMT-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain G [auth B] Focus chain I [auth C] Interactions & Density Focus chain D [auth A] Focus chain G [auth B] Focus chain I [auth C]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain H [auth B] SDF format, chain J [auth C] SDF format, chain K [auth C] MOL2 format, chain E [auth A] MOL2 format, chain H [auth B] MOL2 format, chain J [auth C] MOL2 format, chain K [auth C] mmCIF format, chain E [auth A] mmCIF format, chain H [auth B] mmCIF format, chain J [auth C] mmCIF format, chain K [auth C]	E [auth A], H [auth B], J [auth C], K [auth C]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain E [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain K [auth C] Interactions & Density Focus chain E [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain K [auth C]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
C9G	BindingDB: 6B1K	Ki: 363 (nM) from 1 assay(s)
C9G	BindingDB: 6B1K	Kd: 213 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.17 Å
R-Value Free: 0.154
R-Value Work: 0.135
R-Value Observed: 0.136
Space Group: I 4₁ 2 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 116.904	α = 90
b = 116.904	β = 90
c = 102.188	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
XDS	data processing
XDS	data scaling
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2018-01-03

Deposition Author(s):

Krimmer, S.G.

Robertson, M.J.

Jorgensen, W.L.

Funding Organization	Location	Grant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	United States	GM32136

Revision History (Full details and data files)

Version 1.0: 2018-01-03
Type: Initial release
Version 1.1: 2018-01-17
Changes: Author supporting evidence
Version 1.2: 2020-01-01
Changes: Author supporting evidence
Version 1.3: 2023-10-04
Changes: Data collection, Database references, Refinement description