3NCB: A mutant human Prolactin receptor antagonist H180A in complex with the extracellular domain of the human prolactin receptor

Human prolactin (hPRL), a member of the family of hematopoietic cytokines, functions as both an endocrine hormone and autocrine/paracrine growth factor. We have previously demonstrated that recognition of the hPRL.receptor depends strongly on solution acidity over the physiologic range from pH 6 to pH 8. The hPRL.receptor binding interface contains four histidines whose protonation is hypothesized to regulate pH-dependent receptor recognition. Here, we systematically dissect its molecular origin by characterizing the consequences of His to Ala mutations on pH-dependent receptor binding kinetics, site-specific histidine protonation, and high resolution structures of the intermolecular interface. Thermodynamic modeling of the pH dependence to receptor binding affinity reveals large changes in site-specific protonation constants for a majority of interface histidines upon complexation. Removal of individual His imidazoles reduces these perturbations in protonation constants, which is most likely explained by the introduction of solvent-filled, buried cavities in the crystallographic structures without inducing significant conformational rearrangements.
PDB ID: 3NCBDownload
MMDB ID: 85231
PDB Deposition Date: 2010/6/4
Updated in MMDB: 2010/12
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 3NCB: dimeric; determined by author and by software (PISA)
Molecular Components in 3NCB
Label Count Molecule
Proteins (2 molecules)
Prolactin(Gene symbol: PRL)
Molecule annotation
Prolactin Receptor(Gene symbol: PRLR)
Molecule annotation
Chemicals (5 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB