6CBH

Macrophage Migration Inhibitory Factor in Complex with a Pyrazole Inhibitor (8m)

PDB DOI: https://doi.org/10.2210/pdb6CBH/pdb

Classification: CYTOKINE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2018-02-02 Released: 2018-04-04
Deposition Author(s): Robertson, M.J., Krimmer, S.G., Jorgensen, W.L.
Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), National Science Foundation (NSF, United States)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.214
R-Value Work: 0.173
R-Value Observed: 0.177

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor.

Trivedi-Parmar, V., Robertson, M.J., Cisneros, J.A., Krimmer, S.G., Jorgensen, W.L.

(2018) ChemMedChem 13: 1092-1097

PubMed: 29575754 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/cmdc.201800158
Primary Citation of Related Structures:
6CB5, 6CBF, 6CBG, 6CBH

PubMed Abstract:
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is implicated in the regulation of inflammation, cell proliferation, and neurological disorders. MIF is also an enzyme that functions as a keto-enol tautomerase. Most potent MIF tautomerase inhibitors incorporate a phenol, which hydrogen bonds to Asn97 in the active site. Starting from a 113-μm docking hit, we report results of structure-based and computer-aided design that have provided substituted pyrazoles as phenol alternatives with potencies of 60-70 nm. Crystal structures of complexes of MIF with the pyrazoles highlight the contributions of hydrogen bonding with Lys32 and Asn97, and aryl-aryl interactions with Tyr36, Tyr95, and Phe113 to the binding.

Organizational Affiliation

Department of Chemistry, Yale University, New Haven, CT, 06520-8107, USA.

Macromolecule Content

Total Structure Weight: 38.29 kDa
Atom Count: 3,012
Modelled Residue Count: 342
Deposited Residue Count: 342
Unique protein chains: 1

Macromolecules

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(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 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
EWJ (Subject of Investigation/LOI) Query on EWJ Download Ideal Coordinates CCD File SDF format, chain L [auth C] MOL2 format, chain L [auth C] mmCIF format, chain L [auth C]	L [auth C]	5-(3-fluoro-1H-pyrazol-4-yl)-2-[(naphthalen-2-yl)oxy]benzoic acid C₂₀ H₁₃ F N₂ O₃ DLVKEINOBWQQLX-UHFFFAOYSA-N		Interactions Focus chain L [auth C] Interactions & Density Focus chain L [auth C]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain K [auth C] SDF format, chain M [auth C] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth C] MOL2 format, chain M [auth C] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B] mmCIF format, chain K [auth C] mmCIF format, chain M [auth C]	D [auth A] E [auth A] I [auth B] J [auth B] K [auth C] D [auth A], E [auth A], I [auth B], J [auth B], K [auth C], M [auth C]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth C] Focus chain M [auth C] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth C] Focus chain M [auth C]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A]	G [auth A], H [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain H [auth A] Interactions & Density Focus chain G [auth A] Focus chain H [auth A]
IPA Query on IPA Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain N [auth C] MOL2 format, chain F [auth A] MOL2 format, chain N [auth C] mmCIF format, chain F [auth A] mmCIF format, chain N [auth C]	F [auth A], N [auth C]	ISOPROPYL ALCOHOL C₃ H₈ O KFZMGEQAYNKOFK-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain N [auth C] Interactions & Density Focus chain F [auth A] Focus chain N [auth C]

Binding Affinity Annotations
ID	Source	Binding Affinity
EWJ	BindingDB: 6CBH	Ki: 510 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.214
R-Value Work: 0.173
R-Value Observed: 0.177
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 68.149	α = 90
b = 68.46	β = 90
c = 88.699	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
HKL-2000	data reduction
HKL-2000	data scaling
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2018-04-04

Deposition Author(s):

Robertson, M.J.

Krimmer, S.G.

Jorgensen, W.L.

Funding Organization	Location	Grant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	United States	GM32136
National Science Foundation (NSF, United States)	United States	DGE-1122492

Revision History (Full details and data files)

Version 1.0: 2018-04-04
Type: Initial release
Version 1.1: 2018-06-20
Changes: Data collection, Database references
Version 1.2: 2019-02-20
Changes: Author supporting evidence, Data collection
Version 1.3: 2019-11-27
Changes: Author supporting evidence
Version 1.4: 2024-03-13
Changes: Data collection, Database references