3NCF

A mutant human Prolactin receptor antagonist H30A in complex with the mutant extracellular domain H188A of the human prolactin receptor

Summary for 3NCF

• Entry DOI: 10.2210/pdb3ncf/pdb
• Related: 3MZG 3N06 3N0P 3NCB 3NCC 3NCE
• Descriptor: Prolactin, Prolactin receptor, SODIUM ION, ... (5 entities in total)
• Functional Keywords: ph dependence, hematopoietic cytokine, hormone-hormone receptor complex, hormone/hormone receptor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P01236; Membrane ; Single-pass type I membrane protein . Isoform 7: Secreted: P16471
• Total number of polymer chains: 2
• Total formula weight: 46208.01

Authors

Kulkarni, M.V.,Tettamanzi, M.C.,Murphy, J.W.,Keeler, C.,Myszka, D.G.,Chayen, N.E.,Lolis, E.J.,Hodsdon, M.E. (deposition date: 2010-06-04, release date: 2010-09-29, Last modification date: 2023-09-06)

Primary citation

Kulkarni, M.V.,Tettamanzi, M.C.,Murphy, J.W.,Keeler, C.,Myszka, D.G.,Chayen, N.E.,Lolis, E.J.,Hodsdon, M.E.
Two Independent Histidines, One in Human Prolactin and One in Its Receptor, Are Critical for pH-dependent Receptor Recognition and Activation.
J.Biol.Chem., 285:38524-38533, 2010

PubMed Abstract: 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.

PubMed: 20889499
DOI: 10.1074/jbc.M110.172072

Experimental method

X-RAY DIFFRACTION (2.8 Å)